Pharmacologically active pyridine derivatives and processes for the preparation thereof

ABSTRACT

N-phenyl-2-pyrimidineamine derivatives of formula I ##STR1## wherein the substituents are as defined in claim 1 and the derivatives of formula I can be used, for example, in the treatment of tumour diseases.

This application is filed under 35 U.S.C. §371 as a national phaseapplication of PCT/EP94/03148, filed Sep. 21, 1994.

The invention relates to N-phenyl-4-(4-pyridyl)2-pyrimidineaminederivatives, to processes for the preparation thereof, to medicamentscomprising those compounds, and to the use thereof in the preparation ofpharmaceutical compositions for the therapeutic treatment ofwarm-blooded animals.

The invention relates to N-phenyl2-pyrimidineamine derivatives offormula I ##STR2## wherein R₀ is hydrogen, halogen, lower alkoxy orlower alkyl,

R₁ is

a) N-(amino-lower alkyl)-carbamoyl,

b) N-(hydroxy-lower alkyl)-carbamoyl,

c) hydrazino,

d) cyclohexyl-amino that is unsubstituted or substituted by amino,

e) piperazinyl that is unsubstituted or substituted by amino-loweralkyl,

f) morpholinyl, or

g) lower alkylamino that is substituted by morpholinyl, hydroxy-loweralkylamino, cyano, imidazolyl, guanidyl, amino, lower alkanoylamino,lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl,carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy,lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, loweralkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical ofthe formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl,2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl,4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl,carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or Ris 1H-imidazol-4-yl-methyl, and R₂ is C₁ -C₆ alkyl, C₁ -C₃ alkoxy,chlorine, bromine, iodine, trifluoromethyl, hydroxy, phenyl, amino,mono(C₁ -C₃ alkyl)amino, di(C₁ -C₃ alkyl)amino, C₂ -C₄ alkanoyl,propenyloxy, carboxy, carboxy-methoxy, ethoxycarbonyl-methoxy,sulfanilamido, N,N-di-(C₁ -C₃ alkyl)sulfanilamido, N-methyl-piperazinyl,piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl,1-naphthyl, cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of theformulae:

--CO₂ R₃, --NH--C(═O)--R₃, --N(R₃) --C(═O)--R₄, --O--(CH₂)_(n)--N(R₃)--R₄,

--C(═O)--NH--(CH₂)_(n) --R₄ ^(a), --C(═O)--NH--(CH₂) _(n) --N(R₃)--R₄,--CH(CH₃)--NH--CHO,

--C(CH₃)═N--OH, --C(CH₃)═N--O--CH₃, --CH(CH₃) --NH₂, --NH--CH₂--C(═O)--N(R₃)--R₄, ##STR3## wherein R₃ and R₄ are each independently ofthe other C₁ -C₃ alkyl, R₄ ^(a) is hydroxy, amino or imidazolyl, X isoxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R₅ is hydrogen, C₁ -C₃alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine or trifluoromethyl, R₆is 1H-imidazol-1-yl or morpholinyl and R₇ is C₁ -C₃ alkyl or is phenylthat is unsubstituted or mono-substituted by C₁ -C₃ alkyl, halogen or bytrifluoromethyl, and the salts thereof.

Halogen R₀ is fluorine, bromine, iodine or preferably chlorine.

Lower alkoxy R₀ is preferably methoxy.

Lower alkyl R₀ is preferably methyl.

Amino-lower alkyl in a radical R₁ is preferably ω-amino-C₂ --C₃ alkyl.

Hydroxy-lower alkyl in a radical R₁ is preferably ω-hydroxy-C₂ -C₃alkyl.

Cyclohexyl-amino R₁ substituted by amino is preferably4-amino-cyclohexyl-amino. Di-lower alkylamino-cyclohexyl as part of asubstituted lower alkyl radical R₁ is preferably 4-di-loweralkylamino-cyclohexyl, preferably 4-dimethylamino-cyclohexyl.

Piperazinyl R₁ is preferably 1-piperazinyl. Piperazinyl R₁ substitutedby amino-lower alkyl is preferably 4-(2-amino-ethyl)-piperazin-1-yl.

Morpholinyl R₁ and morpholinyl in a radical R₁ are preferably4-morpholinyl, wherein the free valency extends from the nitrogen. Loweralkylamino R₁ substituted by morpholinyl is preferably2-morpholin-4-yl-ethylamino.

Hydroxy-lower alkylamino in a radical R₁ is preferably2-hydroxy-ethylamino. Lower alkylamino substituted by hydroxy-loweralkylamino is preferably 3-(2-hydroxy-ethyl-amino)-prop-1-ylamino.

Imidazolyl R₄ ^(a) in a radical R₂ is preferably 1H-imidazol-4-yl.

Lower alkanoylamino in a radical R₁ is preferably acetylamino.

Lower alkylamino-carbonylamino in a radical R₁ is preferablymethylamino-carbonyl-amino.

Di-lower alkylamino in a radical R₁ is preferably dimethylamino.

Formyl-piperazinyl in a radical R₁ is preferably 4-formyl-piperazinyl.

Lower alkylamino R₁ substituted by cyano, imidazolyl, guanidyl, amino,lower alkanoyl-amino, lower alkylamino-carbonylamino, amidino, di-loweralkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl,N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy,piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, prolylamidoor by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- is preferablydi- or tri-methylamino substituted by those substituents, thesubstituents preferably being in the ω-position. Lower alkyl R₁substituted by hydroxy can preferably also be 2-hydroxy-propyl.

A radical of the formula H₂ N--CH(R)--C(═O)--, wherein R is as definedabove, is preferably the acyl radical of any one of the following aminoacids which regularly occur in proteins: glycine, alanine, valine,leucine, isoleucine, phenylalanine, serine, threonine, cysteine,methionine, tryptophan, tyrosine, asparagine, glutamine, aspartic acid,glutamic acid, lysine, arginine and histidine, especially in theirnaturally occurring configuration, preferably the (L)-configuration.

Within the scope of this text, the term "lower" denotes radicals havingup to and including 7, preferably up to and including 4, carbon atoms.

Unless otherwise indicated in the context concerned, lower alkyl ispreferably methyl or ethyl.

The compounds of formula I can form acid addition salts, for examplewith inorganic acids, such as hydrochloric acid, sulfuric acid or aphosphoric acid, or with suitable organic carboxylic or sulfonic acids,for example aliphatic mono- or di-carboxylic acids, such astrifluoroacetic acid, acetic acid, propionic acid, glycolic acid,succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malicacid, tartaric acid, citric acid, oxalic acid or amino acids, such asarginine or lysine, aromatic carboxylic acids, such as benzoic acid,2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid,4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such asmandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such asnicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such asmethane-, ethane- or 2-hydroxy-ethane-sulfonic acid, or aromaticsulfonic acids, for example benzene-, p-toluene- ornaphthalene-2-sulfonic acid. Mono, di- or, if other basic groups, suchas amino or guanidyl groups, are present in the radical R₁, poly-acidaddition salts can be formed.

Compounds of formula I having acidic groups, for example a free carboxygroup in the radical R₁, can form metal or ammonium salts, such asalkali metal or alkaline earth metal salts, for example sodium,potassium, magnesium or calcium salts, or ammonium salts with ammonia orsuitable organic amines, such as tertiary monoamines, for exampletriethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, forexample N-ethyl-piperidine or N,N'-dimethyl-piperazine.

Compounds of formula I that possess both acidic and basic groups canform internal salts.

For the purpose of isolation or purification and also in the case of thecompounds used further as intermediates, it is also possible to usepharmaceutically unacceptable salts. Only the pharmaceuticallyacceptable non-toxic salts are used therapeutically, however, and thoseare therefore preferred.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, including also salts that can beused as intermediates, for example in the purification of the novelcompounds or in order to identify those compounds, herein-before andhereinafter any reference to the free compounds is to be understood asincluding also the corresponding salts, where appropriate and expedient.

The compounds of formula I exhibit valuable pharmacological properties:for example, they inhibit the enzyme protein kinase C with a high degreeof selectivity. Phospholipid-and calcium-dependent protein kinase Coccurs in cells in a number of forms and participates in variousfundamental processes, such as signal transmission, proliferation anddifferentiation, and also the release of hormones and neurotransmitters.The activation of that enzyme is effected either by receptor-mediatedhydrolysis of phospholipids of the cell membrane or by directinteraction with certain tumour-promoting active substances. Thesensitivity of the cell to receptor-mediated signal transmission can besubstantially influenced by modifying the activity of protein kinase C(as a signal transmitter). Compounds that are capable of influencing theactivity of protein kinase C can be used as tumour-inhibiting,antiinflammatory, immunomodulating and antibacterial active ingredientsand may even be of value as agents against atherosclerosis and disordersof the cardiovascular system and central nervous system.

Formerly, porcine brain protein kinase C purified in accordance with theprocedure described by T. Uchida and C. R. Filburn in J. Biol. Chem.259, 12311-4 (1984) was used to determine the inhibitory action onprotein kine C, and the inhibitory action on protein kinase C wasdetermined in accordance with the procedure of D. Fabbro et al., Arch.Biochem. Biophys. 239, 102-111 (1985).

The porcine brain protein kinase C formerly used is a mixture of varioussub-types (isotypes) of protein kinase C. If pure recombinant isotypesare used instead of porcine brain protein kinase C in the above test itis found that the compounds of formula I inhibit the "conventional"isotype α preferentially whereas the other "conventional" isotypes β-1,β-2 and γ and especially the "non-conventional" isotypes δ, ε and η andthe "atypical" isoform ζ are generally inhibited to a lesser extent andin some cases hardly at all.

Recombinant PKC isotypes are cloned, expressed and purified in thefollowing manner:

The production of various proteins with the aid of baculoviruses, andtheir cloning and isolation from Sf9 insect cells are carried out asdescribed by M. D. Summers and G. E. Smith, "A manual method forbaculovirus vectors and insect cell culture procedure", Texas Agricul.Exptl. Station Bull. (1987), 1555. The construction and isolation ofrecombinant viruses for the expression of PKC-α (bovine), PKC-β1(human), PKC-β2 (human) and PKC-γ (human/bovine hybrid) in Sf9 cells areeffected in the manner described by Stabel et al. S. Stabel, M. Liyanageand D. Frith, "Expression of protein kinase C isozymes in insect cellsand isolation of recombinant proteins", Meth. Neurosc. (1993)!. Theproduction of the PKC isotypes in Sf9 cells is carried out in the mannerindicated by Stabel et al. (see above), and the purification of theenzymes is effected in accordance with the method described in thepublication by McGlynn et al. E. McGlynn, J. Liebetanz, S. Reutener, J.Wood, N. B. Lydon, H. Hofstetter, M. Vanek, T. Meyer and D. Fabbro,"Expression and partial characterization of rat protein kinase C-δ andprotein kinase C-ζ in insect cells using recombinant baculovirus", J.Cell. Biochem. 49, 239-250 (1992)!. For the generation of recombinantPKC-δ (rat), PKC-ε (rat), PKC-ζ (rat) and PKC-η (mouse), and theirexpression and purification, the procedure described by Liyanage et al."Protein kinase C group B members PKC-δ, -ε, -ζ and PKC-λ: Comparison ofproperties of recombinant proteins in vitro and in vivo", Biochem. J.283, 781-787 (1992)! and McGlynn et al., respectively, (see above) isfollowed, with the additional feature that the transfer vector pAc360 isused for the expression of PKC-η V. Luckow and M. D. Summers, "Trends inthe development of baculovirus expression", Biotechnology 6, 47-55(1988)!.

The measurement of the activity of the recombinant PKC isotypes obtainedby the above method is carried out in the absence of lipid and calcium(co-factors). Protamine sulfate phosphorylated in the absence ofco-factors is used as the substrate. The activity of the enzymesreflects the transfer of ³² P from γ- ³² P!-ATP to protamine sulfate.Protamine sulfate is a mixture of polypeptides each comprising fourC-terminal arginine residues. Phosphate incorporation is measured underthe following conditions: 100 μl of the reaction mixture contain infinal concentrations 20 mM TRIS-HCl pH 7.4, 10 mM Mg NO₃ !₂, 0.5 mg/mlof protamine sulfate, 10 μM ATP (0.1 μCi γ- ³² P!-ATP; 10 Ci/mol;Amersham, Little Chalfont, United Kingdom), various concentrations ofthe inhibitory compounds and 0.5-2.5 U (units: a unit is the amount ofenzyme that, in one minute and per milligram of protein, transfers onenanomole of ³² P from the above-mentioned γ- ³² P!-ATP to histone H1Sigma, type V-S!) of the enzymes. The reaction is started by theaddition of the enzymes and transfer at 32° C. The reaction time is 20minutes. The reaction is then stopped by dripping aliquots of 50 μl ontoP81 chromatography paper (Whatman, Maidstone, United Kingdom). Afterremoving unbound γ- ³² P!-ATP and nucleotide fragments by washingoperations as described by J. J. Witt and R. Roskoski, "Rapid proteinkinase assay using phospho-cellulose-paper absorption", Anal. Biochem.66, 253-258 (1975), the substrate phosphorylation is determined byscintillation measurement. In that test, the compounds of formula Iinhibit the α-isotype of protein kinase C (PKC) at an IC₅₀ of as low asapproximately from 0.1 to 5.0 μmol/litre, generally approximately from0.1 to 1.0 μmol/litre. In contrast, the other isotypes of PKC aregenerally inhibited only at distinctly higher concentrations (i.e. atconcentrations up to more than 300 times higher).

As may be expected purely on the basis of the above-described inhibitoryaction on protein kinase C, the compounds of formula I exhibitantiproliferative properties which can be demonstrated directly inanother test described in the following in which the inhibitory actionof the compounds of formula I on the growth of human T24 bladdercarcinoma cells is determined. Those cells are incubated in Eagle'sminimal essential medium, to which 5% (v/v) fetal calf serum has beenadded, in a humidified incubator at 37° C. and with 5% by volume of CO₂in the air. The carcinoma cells (1000-1500) are sown in 96-wellmicrotitre plates and incubated overnight under the above-mentionedconditions. The test compound is added in serial dilutions on day 1. Theplates are incubated for 5 days under the above-mentioned conditions.During that period the control cultures undergo at least four celldivisions. After incubation, the cells are fixed with 3.3% (w/v) aqueousglutaraldehyde solution, washed with water and stained with 0.05%(weight/volume) aqueous methylene blue solution. After washing, the dyeis eluted with 3% (w/v) aqueous hydrochloric acid. The optical density(OD) per well, which is directly proportional to the number of cells, isthen measured at 665 nm using a photometer (Titertek multiskan). TheIC₅₀ values are calculated with a computer system using the formula##EQU1##

The IC₅₀ values are defined as being the concentration of activeingredient at which the number of cells per well at the end of theincubation period is only 50% of the number of cells in the controlcultures. In the case of the compounds of formula I, the IC₅₀ values soascertained are approximately from 0.01 to 10 μmol/litre, generallyapproximately from 0.01 to 1 μmol/litre.

The anti-tumour activity of the compounds of formula I can also bedemonstrated in vivo:

Female Balb/c hairless mice with s.c. transplanted human bladder tumoursT24 are used to determine the anti-tumour activity. On day 0, with theanimals under peroral forene narcosis, approximately 25 mg of a solidtumour are placed under the skin on the animals' left flank and thesmall incised wound is closed by means of suture clips. On day 6 afterthe transplantation, the mice are divided at random into groups of 6animals and treatment commences. The treatment is carried out for 15days with peroral or intraperitoneal administration once daily of acompound of formula I in dimethyl sulfoxide/Tween 80/-sodium chloridesolution in the various doses. The tumours are measured twice a weekwith a slide gauge and the volume of the tumours is calculated. In thattest, the peroral or intraperitoneal administration of a compound offormula I brings about a marked reduction in the average tumour volumein comparison with the untreated control animals.

On the basis of the properties described, the compounds of formula I canbe used especially as tumour-inhibiting active ingredients, for examplein the treatment of tumours of the bladder and the skin. When thecompounds of formula I are used in the treatment of cancer incombination with other chemotherapeutic drags, they prevent thedevelopment of resistance (multidrug resistance) or eliminate an alreadyexisting resistance to the other chemotherapeutic drugs. They are alsosuitable for the other uses mentioned above for protein kinase Cmodulators and can be used especially in the treatment of disordersresponsive to inhibition of protein kinase C.

Some of the compounds of formula I also inhibit the tyrosine kinaseactivity of the receptor for the epidermal growth factor (EGF). Thatreceptor-specific enzyme activity plays a key role in signaltransmission in a large number of mammalian cells, including humancells, especially epithelial cells, cells of the immune system and cellsof the central and peripheral nervous system. In the case of varioustypes of cell, the EGF-induced activation of the receptor-associatedtyrosine protein kinase (EGF-R-TPK) is a prerequisite for cell divisionand accordingly for the proliferation of a cell population. The additionof EGF-receptor-specific tyrosine kinase inhibitors thus inhibits thereplication of those cells.

Inhibition of EGF-receptor-specific tyrosine protein kinase (EGF-R-TPK)can be demonstrated, for example, using the method of E. McGlynn et at.,Europ. J. Biochem. 207, 265-275 (1992). The compounds according to theinvention inhibit the enzyme activity by 50% (IC50) for example at aconcentration of from 0.1 to 10 μM.

The compounds of formula I that inhibit the tyrosine kinase activity ofthe receptor for the epidermal growth factor (EGF) can accordingly beused, for example, in the treatment of benign or malignant tumours. Theyare able to bring about tumour regression and to prevent metastaticspread and the growth of micrometastases. They can be used especially inthe case of epidermal hyperproliferation (psoriasis), in the treatmentof neoplasia of epithelial character, for example mastocarcinoma, and inthe case of leukaemia. The compounds can also be used in the treatmentof disorders of the immune system and inflammation if protein kinasesare involved. Furthermore, those compounds of formula I can be used inthe treatment of disorders of the central or peripheral nervous systemif signal transmission by protein kinases is involved.

The compounds of formula I and the salts thereof also inhibit the enzymep34^(cdc2) /cycline B^(cdc13) kinase. That kinase controls, in additionto other cdc2-related kinases, specific phases of cell division,especially the transition from the G₁ -phase to the S-phase and moreespecially the transition from the G₂ -phase to the M-phase.

In chronological order, the cycle of a eukaryotic cell consists of theinterphase and the M-phase. The interphase is accompanied by an increasein the size of the cell. In chrono-logical order, the interphaseconsists for its part of the G₁ -phase, the S-phase and the G₂ -phase.In the G₁ -phase (G=gap) biosynthetic processes take place in the cell.In the S-phase (synthesis phase) the DNA doubles. The cell then entersthe G₂ -phase which ends with the commencement of mitosis.

In chronological order, the M-phase for its part consists of thedivision of the cell nucleus (mitosis) and the division of the cytoplasm(cytokinesis).

The above-mentioned inhibition of the enzyme p34^(cdc2) /cyclineB^(cdc13) kinase can be demonstrated by the following test:

10 μM 1-methyl-adenine are used to induce starfish oocytes to enter theM-phase. The oocytes are then frozen in liquid nitrogen and stored at-80° C. If necessary, the oocytes are homogenised and centrifuged, asdescribed in D. Arion et al., Cell 55,371-378 (1988) and V. Rialet andL. Meijer, Anticancer Res. 11, 1581-1590 (1991). In order to purify thep34^(cdc2) /cycline B^(cdc13) kinase, the supernatant of the oocytes isadded to p9^(CKShs) -Sepharose grains prepared from recombinant humanprotein p9^(CKShs), as described in L. Azzi et al., Eur. J. Biochem.203, 353-360 (1992). After 30 minutes at 4° C. while being turnedconstantly, the grains are washed thoroughly and the active p34^(cdc2)/cycline B^(cdc13) kinase is eluted with free protein p9^(CKShs) (3mg/ml). The eluted kinase is tested using histone H₁ as substrate, asdescribed in L. Meijer et at., EMBO J. 8, 2275-2282 (1989) and EMBO J.10, 1545-1554 (1991). In that test, the compounds of formula I and theirsalts exhibit an inhibiting concentration IC₅₀ μmol/litre! ofapproximately from 0.0005 to 2, in most cases approximately from 0.001to 0.4.

That finding would also lead to the expectation that the compounds offormula I and the salts thereof can be used in the treatment ofhyperproliferative disorders, such as tumours and psoriasis.

The compounds of formula I also inhibit the production of HIV viruses,as shown by the test below, and can accordingly be used as agentsagainst the immune deficiency disease AIDS. The initial symptomsobserved after HIV infection in humans is followed by a clinical latencyperiod which can last several years. After that period, the stage knownas AIDS occurs and usually progresses to death. The latency period isattributed to several factors: immune response, occlusion of the virusesin lymph nodes or other tissue and entry into a stage of molecular andviral latency in which the infected cells do not complete the vital cellcycle, which is why infectious viruses cannot be produced and theinfection cannot spread. That stage of molecular latency has beeninvestigated using cell models, such as the ACH-2 cell line K. Clouse etal., J. Immunol. 142, 431 (1989)! and the U1 cell line T. Folks et al.,J. Immunol. 140, 117 (1988)!. Those cells are infected with HIV-1viruses, but have only a low content of infectious viruses. If, however,those cells are stimulated with physiologically relevant factors thatare known to be increased in AIDS patients, such as tumour necrosisfactor, interleukin-6 etc., or with chemical inductors, such as phorboldiesters, for example 13-O-acetyl-12-O-n-tetradecanoyl-phorbol, amassive production of virus follows. The ACH-2 and U 1 cells arerepresentatives of two different cell families that are targets for HIVinfection, namely lymphocytes and macro-phages.

Hitherto, effective prevention of the progression of HIV infection tothe outbreak of AIDS has not been possible. Many attempts have been madeto prevent virus replication after the outbreak of AIDS, that is to say,in a stage in which viruses are produced on a massive scale. Incontrast, the compounds of formula I interfere with cell processes thatlead to the activation of latently infected HIV cells without impairingnormal cell processes, such as cell division.

If the above-mentioned U1 or ACH-2 cells are used as a model for virallatency, it can be demonstrated that HIV virus production induced by13-O-acetyl-12-O-n-tetradecanoylphorbol or tumour necrosis factor-alphaare effectively inhibited by the compounds of formula I at aconcentration of approximately from 0.001 to 1 μmol/litre, for exampleat 0.03 μmol/litre.

Preferred are compounds of formula Ia ##STR4## wherein R₁ is

a) N-(amino-lower alkyl)-carbamoyl,

b) N-(hydroxy-lower alkyl)-carbamoyl,

c) hydrazino,

d) cyclohexyl-amino that is unsubstituted or substituted by amino, or

e) lower alkylamino that is substituted by cyano, imidazolyl, guanidyl,amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino,di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl,carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy,dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl,formylpiperazinyl, prolylamido or by a radical of the formula H₂N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl,hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl,indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl,carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl,4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and

R₂ is C₁ -C₆ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine,trifluoromethyl, hydroxy, phenyl, amino, mono(C₁ -C₃ alkyl)amino, di(C₁-C₃ alkyl)amino, C₂ -C₄ alkanoyl, propenyloxy, carboxy, carboxy-methoxy,ethoxycarbonyl-methoxy, sulfanilamido, N,N-di(C₁ -C₃alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl,1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl,cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formulae:

--CO₂ R₃, --NH--C(═O)--R₃, --N(R₃)--C(═O)--R₄, --O--(CH₂)_(n)--N(R₃)--R₄, --C(═O)--NH--(CH₂)_(n) --N(R₃)--R₄, --CH(CH₃)--NH--CHO,--C(CH₃)═N--OH, --C(CH₃)═N--O--CH₃, --CH(CH₃)--NH₂, --NH--CH₂--C(═O)--N(R₃)--R₄, ##STR5## wherein R₃ and R₄ are each independently ofthe other C₁ -C₃ alkyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or3, R₅ is hydrogen, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, chlorine, bromine,iodine or trifluoromethyl, R₆ is 1H-imidazol-1-yl or morpholinyl and R₇is C₁ -C₃ alkyl or is phenyl that is unsubstituted or mono-substitutedby C₁ -C₃ alkyl, halogen or by trifluoromethyl, and the salts thereof.

A preferred group comprises compounds of formula I wherein

R₀ is hydrogen, halogen, lower alkoxy or lower alkyl,

R₁ is

a) N-(amino-lower alkyl)-carbamoyl,

b) N-(hydroxy-lower alkyl)-carbamoyl,

c) hydrazino,

d) piperazinyl that is unsubstituted or substituted by amino-loweralkyl,

e) morpholinyl, or

f) lower alkylamino that is substituted by morpholinyl, hydroxy-loweralkylamino, imidazolyl, guanidyl, amino, lower alkanoylamino, loweralkylamino-carbonylamino, amidino, carboxy, lower alkoxycarbonyl,carbamoyl, N-hydroxy-carbamoyl, hydroxy, dihydroxyphosphoryloxy or by aradical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen,and

R₂ is chlorine, trifluoromethyl, carboxy, a radical of the formula --CO₂R₃ wherein R₃ is C₁ -C₃ alkyl, or a radical of the formula--C(═O)--NH--(CH₂) _(n) --R₄ ^(a) wherein n is 2 or 3 and R₄ ^(a)wherein n 2 or 3 and R₄ ^(a) is hydroxy, amino or imidazolyl, and thesalts thereof.

A further preferred group comprises compounds of formula I wherein

R₀ is hydrogen,

R₁ is

a) N-(amino-lower alkyl)-carbamoyl,

b) N-(hydroxy-lower alkyl)-carbamoyl,

c) hydrazino or

d) lower alkylamino that is substituted by imidazolyl, guanidyl, amino,lower alkanoyl-amino, lower alkylamino-carbonylamino, amidino, carboxy,lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy,dihydroxyphosphoryloxy or by a radical of the formula H₂N--CH(R)--C(═O)--NH-- wherein R is hydrogen, and

R₂ is chlorine or trifluoromethyl, and the salts thereof.

Preferred are compounds of formula I wherein

R₀ is hydrogen, chlorine, lower alkyl or lower alkoxy,

R₁ is N-(ω-amino-C₂ -C₃ alkyl)-carbamoyl, N-(ωhydroxy-C₂ -C₃alkyl)-carbamoyl, hydrazino, 2-hydroxy-propylamino or linear C₂ -C₃alkylamino that is substituted in the ω-position by morpholinyl,ω-hydroxy-lower alkylamino, imidazolyl, guanidyl, amino, loweralkanoylamino, amidino, carboxy, lower alkoxycarbonyl, carbamoyl,N-hydroxycarbamoyl, hydroxy or by dihydroxyphosphoryloxy, and

R₂ is chlorine, trifluoromethyl, carboxy, a radical of the formula --CO₂R₃ wherein R₃ is C₁ -C₃ alkyl, or a radical of the formula--C(═O)--NH--(CH₂) _(n) --R₄ ^(a) wherein n is 2 or 3 and R₄ ^(a) ishydroxy, amino or imidazolyl, and the salts thereof.

Preferred are especially compounds of formula I wherein

R₀ is hydrogen,

R₁ is N-(ω-amino-C₂ -C₃ alkyl)-carbamoyl, N-(ω-hydroxy-C₂ -C₃alkyl)-carbamoyl, hydrazino, 2-hydroxy-propylamino or linear C₂ -C₃alkylamino that is substituted in the ω-position by imidazolyl,guanidyl, amino, lower alkanoylamino, amidino, carboxy, loweralkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy or bydihydroxyphosphoryloxy, and

R₂ is chlorine or trifluoromethyl, and the salts thereof.

Especially preferred are compounds of formula I wherein

R₀ is hydrogen, chlorine, methyl or methoxy,

R₁ is N-(ω-amino-C₂ -C₃ alkyl)-carbamoyl, N-(ω-hydroxy-C₂ -C₃alkyl)-carbamoyl, hydrazino, 2-hydroxy-propylamino or linear C₂ -C₃alkylamino that is substituted in the ω-position by 4-morpholinyl,ω-hydroxy-ethylamino, 1H-imidazol-1-yl, 1H-imidazol-4-yl, guanidyl,amino, acetylamino, amidino, carboxy, ethoxycarbonyl, carbamoyl,N-hydroxycarbamoyl, hydroxy or dihydroxyphosphoryloxy, and

R₂ is chlorine, trifluoromethyl, carboxy, a radical of the formula --CO₂R₃ wherein R₃ is methyl, or a radical of the formula --C(═O)--NH--(CH₂)_(n) --R₄ ^(a) wherein n is 2 or 3 and R₄ ^(a) is hydroxy, amino or1H-imidazol-4-yl, and the salts thereof.

More especially preferred are the compounds of formula I described inthe Examples.

The compounds of formula I and the salts thereof are prepared inaccordance with processes known per se. The process according to theinvention for the preparation of an N-phenyl-2-pyrimidineaminederivative of formula I is effected as follows:

a) a compound of formula II ##STR6## wherein R₈ and R₉ are eachindependently of the other lower alkyl and R₁ is as defined above,functional groups present in a compound of formula II, with theexception of the groups participating in the reaction, being, ifnecessary, in protected form, or a salt of such a compound is reactedwith a compound of formula III ##STR7## wherein R₀ and R₂ are as definedabove, functional groups present in a compound of formula III, with theexception of the guanidino group participating in the reaction, being,if necessary, in protected form, or with a salt of such a compound, andany protecting groups present are removed, or

b) for the preparation of a compound of formula I wherein R₁ has theabove-mentioned meaning c), d) or g) and R₀ and R₂ each have any one ofthe above-mentioned meanings, a compound of formula IV ##STR8## whereinY is a leaving group and R₀ and R₂ are as defined above, functionalgroups present in a compound of formula IV, with the exception of theleaving group participating in the reaction, being, if necessary, inprotected form, or a salt of such a compound is reacted with an amine ofthe formula

    H.sub.2 N--R.sub.12                                        (V)

wherein R₁₂ is amino or unsubstituted or amino-substituted cyclohexyl,or is lower alkyl that is substituted by morpholinyl, hydroxy-loweralkylamino, cyano, imidazolyl, guanidyl, amino, lower alkanoylamino,lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl,carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxycarbamoyl, hydroxy,lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, loweralkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical ofthe formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl,2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl,4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl,carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or Ris 1H-imidazol-4-yl-methyl, functional groups present in R₁₂ being, ifnecessary, in protected form, and any protecting groups present areremoved, or

c) for the preparation of a compound of formula I wherein R₁ isN-(amino-lower alkyl)-carbamoyl or N-(hydroxy-lower alkyl)-carbamoyl andR₀ and R₂ each have any one of the above-mentioned meanings, acarboxylic acid of formula IX ##STR9## wherein R₀ and R₂ each have anyone of the above-mentioned meanings, functional groups present in R₂being, if necessary, in protected form, or a reactive acid derivativethereof is reacted with an amine of formula X

    H.sub.2 N--R.sub.13                                        (X),

wherein R₁₃ is amino-lower alkyl or hydroxy-lower alkyl, the amino orhydroxy group being, if necessary, in protected form, and any protectinggroups present are removed, or

d) for the preparation of a compound of formula I wherein R_(l) ismorpholinyl, or is piperazinyl that is unsubstituted or substituted byamino-lower alkyl and R₀ and R₂ each have any one of the above-mentionedmeanings, a compound of formula IV ##STR10## wherein Y is a leavinggroup and R₀ and R₂ are as defined above, functional groups present in acompound of formula IV, with the exception of the leaving groupparticipating in the reaction, being, if necessary, in protected form,or a salt of such a compound is reacted with morpholine, or withpiperazine that is unsubstituted or substituted by amino-lower alkyl,and any protecting groups present are removed, or

e) for the preparation of a compound of formula I wherein R₂ is --CO₂R₃, --C(═O)--NH--(CH₂)_(n) --R₄ ^(a) or --C(═O)--NH--(CH₂)_(n)--N(R₃)--R₄, wherein the symbols and substituents are each as definedabove, a carboxylic acid of formula XI ##STR11## wherein R₀ and R₁ areas defined above, functional groups present therein being, if necessary,in protected form, or a reactive carboxylic acid derivative thereof isesterified or amidated in an appropriate manner and any protectinggroups present are removed, and, if desired, a compound of formula Iobtained in accordance with any one of Processes a-e is convened intoits salt, or an obtained salt of a compound of formula I is convenedinto the free compound.

The manner in which the above-mentioned process variants are carried outis explained in detail hereinafter:

General:

The end products of formula I may comprise substituents that can also beused as protecting groups in starting materials for the preparation ofother end products of formula I. Within the scope of this text,therefore, unless the context indicates otherwise, only a readilyremovable group that is not a constituent of the particular end productof formula I desired is referred to as a "protecting group".

Protecting groups and the manner in which they are introduced andremoved are described, for example, in "Protective Groups in OrganicChemistry", Plenum Press, London, New York 1973, and in "Methoden derorganischen Chemie", Houben-Weyl, 4th edition, Vol. 15/1,Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene,"Protective Groups in Organic Synthesis", John Wiley & Sons, New York1981. A characteristic of protecting groups is that they can be readilyremoved, that is to say, without undesired secondary reactions takingplace, for example by solvolysis, reduction, photolysis or also underphysiological conditions.

Hydroxy-protecting groups are, for example, acyl radicals, such asunsubstituted or substituted, for example halogen-substituted, loweralkanoyl, such as 2,2-dichloroacetyl, or acyl radicals of carbonic acidsemiesters, especially tert-butoxycarbonyl, unsubstituted or substitutedbenzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, ordiphenylethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as2,2,2-trichloroethoxycarbonyl, and also trityl or formyl, or organicsilyl or stannyl radicals, and also readily removable etherifyinggroups, such as tert-lower alkyl, for example tert-butyl, 2-oxa- or2-thia-aliphatic or -cycloaliphatic hydrocarbon radicals, especially1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, for examplemethoxymethyl, 1-methoxy-ethyl, 1-ethoxyethyl, methylthiomethyl,1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-11thia-cycloalkylhaving 5 or 6 ring atoms, for example tetrahydrofuryl or2-tetrahydropyranyl or corresponding thia analogues, and alsounsubstituted or substituted 1-phenyl-lower alkyl, such as unsubstitutedor substituted benzyl or diphenylmethyl, suitable substituents of thephenyl radicals being, for example, halogen, such as chlorine, loweralkoxy, such as methoxy, and/or nitro.

A protected amino group may, for example, be in the form of a readilycleavable acyl-amino, arylmethylamino, etherified mercaptoamino,2-acyl-lower alk-1-en-yl-amino, silyl-amino or stannylamino group or inthe form of an azido group.

In a corresponding acylamino group, acyl is, for example, the acylradical of an organic carboxylic acid having, for example, up to 18carbon atoms, especially of an alkane-carboxylic acid that isunsubstituted or substituted, for example, by halogen or by aryl, or ofa benzoic acid that is unsubstituted or substituted, for example, byhalogen, lower alkoxy or by nitro, or of a carbonic acid semiester. Suchacyl groups are, for example, lower alkanoyl, such as formyl, acetyl orpropionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or2,2,2-trichloro-acetyl, benzoyl that is unsubstituted or substituted,for example, by halogen, lower alkoxy or by nitro, for example benzoyl,4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or loweralkoxycarbonyl that is branched in the 1-position of the lower alkylradical or suitably substituted in the 1- or 2-position, especiallytert-lower alkoxycarbonyl, for example tert-butoxycarbonyl,arylmethoxycarbonyl having one or two aryl radicals that are preferablyphenyl that is unsubstituted or mono- or poly-substituted, for example,by lower alkyl, especially tert-lower alkyl, such as tert-butyl, loweralkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and/orby nitro, such as unsubstituted or substituted benzyloxycarbonyl, forexample 4-nitrobenzyloxycarbonyl, or substituteddiphenylmethoxycarbonyl, for example benzhydryloxycarbonyl ordi(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl wherein thearoyl group is preferably benzoyl that is unsubstituted or substituted,for example, by halogen, such as bromine, for examplephenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)-ethoxycarbonyl whereinthe substituents are each independently of the others an aliphatic,araliphatic, cycloaliphatic or aromatic hydrocarbon radical that isunsubstituted or substituted, for example, by lower alkyl, lower alkoxy,aryl, halogen or by nitro, and contains up to 15 carbon atoms, such ascorresponding unsubstituted or substituted lower alkyl, phenyl-loweralkyl, cycloalkyl or phenyl, for example 2-tri-loweralkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

Other acyl radicals suitable as amino-protecting groups are alsocorresponding radicals of organic phosphoric, phosphonic or phosphinicacids, such as di-lower alkylphosphoryl, for example dimethylphosphoryl,diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl,dicycloalkylphosphoryl, for example dicyclohexylphosphoryl,unsubstituted or substituted diphenylphosphoryl, for examplediphenylphosphoryl, unsubstituted or substituted, for examplenitro-substituted, di(phenyl-lower alkyl)phosphoryl, for exampledibenzylphosphoryl or di(4-nitrobenzyl)phosphoryl, unsubstituted orsubstituted phenyloxyphenylphosphonyl, for examplephenyloxyphenylphosphonyl, di-lower alkylphosphinyl, for examplediethylphosphinyl, or unsubstituted or substituted diphenylphosphinyl,for example diphenylphosphinyl.

In an arylmethylamino group that is a mono-, di- or, especially,tri-arylmethylamino group, the aryl radicals are especiallyunsubstituted or substituted phenyl radicals. Such groups are, forexample, benzyl-, diphenylmethyl- and, especially, trityl-amino.

An etherified mercapto group in an amino group protected by such aradical is especially arylthio or aryl-lower alkylthio wherein aryl isespecially phenyl that is unsubstituted or substituted, for example, bylower alkyl, such as methyl or tert-butyl, lower alkoxy, such asmethoxy, halogen, such as chlorine, and/or by nitro. A correspondingamino-protecting group is, for example, 4-nitrophenylthio.

In a 2-acyl-lower alk-1-en-1-yl radical that can be used as anamino-protecting group, acyl is, for example, the corresponding radicalof a lower alkanecarboxylic acid, of a benzoic acid that isunsubstituted or substituted, for example, by lower alkyl, such asmethyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such aschlorine, and/or by nitro, or especially of a carbonic acid semiester,such as a carbonic acid lower alkyl semiester. Corresponding protectinggroups are especially 1-lower alkanoyl-prop-1-en-2-yl, for example1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, forexample 1-ethoxycarbonyl-prop-1-en-2-yl.

Preferred amino-protecting groups are acyl radicals of carbonic acidsemiesters, especially tert-butoxycarbonyl, benzyloxycarbonyl that isunsubstituted or substituted, for example, as indicated, for example4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-loweralkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, and also tritylor formyl. The removal of the protecting groups that are notconstituents of the desired end product of formula I is effected in amanner known per se, for example by solvolysis, especially hydrolysis,alcoholysis or acidolysis, or by means of reduction, especiallyhydrogenolysis or chemical reduction, as appropriate stepwise orsimultaneously.

A protected amino group is freed in a manner known per se and, dependingon the nature of the protecting groups, in various manners, preferablyby solvolysis or reduction. 2-halo-lower alkoxycarbonylamino (whereappropriate after conversion of a 2-bromo-lower alkoxycarbonylaminogroup into a 2-iodo-lower alkoxycarbonylamino group),aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can becleaved, for example, by treatment with a suitable chemical reducingagent, such as zinc in the presence of a suitable carboxylic acid, suchas aqueous acetic acid. Aroylmethoxycarbonylamino can also be cleaved bytreatment with a nucleophilic, preferably saltforming reagent, such assodium thiophenolate, and 4-nitro-benzyloxycarbonylamino also bytreatment with an alkali metal dithionite, for example sodiumdithionite. Unsubstituted or substituted diphenylmethoxycarbonylamino,tert-lower alkoxycarbonylamino or 2-tri-substitutedsilylethoxycarbonylamino can be cleaved by treatment with a suitableacid, for example formic acid or trifluoroacetic acid, unsubstituted orsubstituted benzyloxycarbonylamino, for example, by hydrogenolysis, thatis to say by treatment with hydrogen in the presence of a suitablehydrogenation catalyst, such as a palladium catalyst, unsubstituted orsubstituted triarylmethylamino or formylamino, for example, by treatmentwith an acid, such as a mineral acid, for example hydrochloric acid, oran organic acid, for example formic, acetic or trifluoroacetic acid,where appropriate in the presence of water, and an amino group protectedby an organic silyl group can be freed, for example, by hydrolysis oralcoholysis. An amino group protected by 2-haloacetyl, for example2-chloroacetyl, can be freed by treatment with thiourea in the presenceof a base, or with a thiolate salt, such as an alkali metal thiolate, ofthe thiourea, and subsequent solvolysis, such as alcoholysis orhydrolysis, of the resulting condensation product. An amino groupprotected by 2-substituted silylethoxycarbonyl can also be convened intothe free amino group by treatment with a hydrofluoric acid salt yieldingfluoride anions.

A hydroxy group protected by a suitable acyl group, an organic silylgroup or by unsubstituted or substituted 1-phenyl-lower alkyl is freedanalogously to a correspondingly protected amino group. Hydroxyprotected by unsubstituted or substituted 1-phenyl-lower alkyl, forexample benzyl, is freed preferably by catalytic hydrogenation, forexample in the presence of a palladium-on-carbon catalyst. A hydroxygroup protected by 2,2-dichloroacetyl is freed, for example, by basichydrolysis, and a hydroxy group etherified by tert-lower alkyl or by a2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical isfreed by acidolysis, for example by treatment with a mineral acid or astrong carboxylic acid, for example trifluoroacetic acid. Hydroxyetherified by an organic silyl radical, for example trimethylsilyl, canalso be freed by a hydrofluoric acid salt yielding fluoride anions, forexample tetrabutylammonium fluoride.

Process a:

Preferably, R₈ and R₉ are each methyl.

Free functional groups in a compound of formula II, which areadvantageously protected by readily removable protecting groups, areespecially amino groups in the radical R₁ and the imino group of1H-indolyl. The imino group can be protected, for example, by benzyl.

Free functional groups in a compound of formula III, which areadvantageously protected by readily removable protecting groups, areespecially amino groups, but also hydroxy and carboxy groups.

A salt of a compound of formula II or III is preferably an acid additionsalt, for example a nitrate or one of the acid addition salts mentionedfor the end products of formula I.

The reaction is carried out in a suitable solvent or dispersing agent,for example a suitable alcohol, such as 2-methoxy-ethanol or a suitablelower alkanol, for example isopropanol or isobutanol, at a temperatureof from room temperature (approximately 20° C.) to 150° C., for exampleunder reflux. Especially when a compound of formula II or especially IIIis used as salt, that salt is converted into the free compound,preferably in situ, by the addition of a suitable base, such as analkali metal hydroxide, for example sodium hydroxide.

The starting material of formula II is obtained by reacting a compoundof formula VI ##STR12## wherein R₁ is as defined above, functionalgroups present therein being, if necessary, in protected form, or a saltof such a compound with a compound of formula VII ##STR13## wherein R₁₀and R₁₁ are each lower alkyl and the other substituents are as definedabove, analogously to the procedure described in the European PatentApplication having the publication number 233 461. Typicalrepresentatives of a compound of formula VII are N,N-dimethylformamidedimethylacetal and N,N-dimethylformamide diethylacetal. The reaction iseffected while heating the reactants of formulae VI and VII, for examplefor 1-24 hours, in the absence or, if necessary, in the presence of asolvent, at a temperature of approximately from 50° C. to 150° C., forexample at approximately 110° C.

Alternatively, the starting material of formula II can also be obtainedby reacting a compound of formula VI with formic acid ethyl ester of theformula H--C(═O)--O--CH₂ --CH₃ and reacting the resulting product withan amine of the formula H--N(R₈)--R₉ wherein the substituents are asdefined above.

The starting material of formula III is obtained in the form of an acidaddition salt by reacting an aniline derivative of formula VIII##STR14## wherein R₀ and R₂ are as defined above, with cyanamide(NC--N₂). The reaction is effected in a suitable solvent or dispersingagent, for example a suitable alcohol, for example a suitable loweralkanol, such as ethanol, for example

α) in the presence of equimolar amounts of the salt-forming acid, forexample nitric acid, or

β) in the presence of a clear, for example 60%, excess of a mineralacid, such as hydrochloric acid, an ammonium salt of the desiredsalt-forming acid, for example ammonium nitrate, being added when thereaction is complete, at a temperature of from room temperature to 150°C., for example under reflux.

Process b:

A leaving group Y in a compound of formula IV is reactive esterifiedhydroxy, for example hydroxy esterified by a strong inorganic or organicacid, such as by a mineral acid, for example a hydrohalic acid, such ashydrochloric, hydrobromic or hydriodic acid, also sulfuric acid or asulfuryl halide, for example sulfuryl fluoride, or by a strong organicsulfonic acid, such as a lower alkanesulfonic acid that is unsubstitutedor substituted, for example, by halogen, such as fluorine, or anaromatic sulfonic acid, for example a benzenesulfonic acid that isunsubstituted or substituted by lower alkyl, such as methyl, halogen,such as bromine, and/or by nitro, for example a methanesulfonic,trifluoromethanesulfonic or p-toluenesulfonic acid. Y is preferablyhalogen, such as, especially, chlorine.

The reaction is preferably carded out in the presence of an excess ofthe amine of formula V, which can, where appropriate, also be used assolvent, and, if necessary, in the presence of an inert solvent, such asdimethyl sulfoxide, at a temperature of from room temperature to +150°C., for example at 100° C.

The starting material of formula IV can be prepared, for example,analogously to Process a. For example, first 4-acetyl-pyridine can beoxidised with m-chloro-perbenzoic acid in a suitable solvent, such asmethylene chloride, for example under reflux, to 4-acetylpyridineN-oxide. 4-acetyl-pyridine N-oxide is then convened with phosphorusoxychloride in a suitable inert solvent, such as toluene, for example atapproximately 100° C., into 4-acetyl-2-chloro-pyridine. The4-acetyl-2-chloro-pyridine obtained is then reacted with a compound offormula VII shown in Process a to give a compound analogous to formulaII shown above under Process a wherein R₁ is chlorine. The compound soobtained is then reacted analogously to Process a with a compound offormula III to form the starting material of formula IV.

Alternatively, the starting material of formula IV can be obtained byconverting 4-acetylpyridine N-oxide with dimethylformamide diethylacetalof formula VII, which, for example, simultaneously serves as solvent,for example at approximately 110° C., into3-dimethylamino-1-(N-oxido-pyridyl)-2-propen-1-one, such as3-dimethylamino-1-(N-oxido-4-pyridyl)-2-propen-1-one, which is thenreacted with an R₂ -phenyl-guanidine of formula III wherein R₂ is asdefined above, or preferably with a suitable salt, for example a nitram,thereof in a suitable solvent, such as isopropanol, and in the presenceof a suitable base, such as sodium hydroxide, for example under reflux,to form an N-oxidopyridyl compound analogous to formula IV wherein Y isoxido. The N-oxido-pyridyl compound so obtained is then converted withphosphorus oxychloride into a compound of formula IV wherein Y ischlorine. The reaction with phosphorus oxychloride can be carried out,for example, in the absence of a solvent at approximately 100° C.Alternatively, it is possible to use phosphorus oxychloride togetherwith a suitable amine, such as diisopropylamine in a suitable solvent,for example a chlorinated hydrocarbon, such as chloroform, atapproximately room temperature. Another possibility is to use phosphorusoxychloride in a suitable solvent, such as chloroform, toluene orxylene, at elevated temperature, for example under reflux.

Process c:

Free functional groups in the radical R₂ of a compound of formula IX,which are advantageously protected by readily removable protectinggroups, are especially carboxy groups, but also amino groups.

A reactive derivative of a compound of formula IX is especially areactive (activated) ester, a reactive anhydride or a reactive cyclicamide.

Reactive (activated) esters of an acid of formula IX are especiallyesters unsaturated at the linking carbon atom of the esterifyingradical, for example of the vinyl ester type, such as vinyl estersthemselves (which can be obtained, for example, by transesterifying acorresponding ester with vinyl acetate; activated vinyl ester method),carbamoyl vinyl esters (which can be obtained, for example, by treatingthe corresponding acid with an isoxazolium reagent; 1,2-oxazolium orWoodward method), or 1-lower alkoxyvinyl esters (which can be obtained,for example, by treating the corresponding acid with a loweralkoxyacetylene; ethoxyacetylene method), or esters of the amidino type,such as N,N'-di-substituted amidino esters (which can be obtained, forexample, by treating the corresponding acid with a suitableN,N'-di-substituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide; carbodiimide method), orN,N-di-substituted amidino esters (which can be obtained, for example,by treating the corresponding acid with an N,N-di-substituted cyanamide;cyanamide method), suitable aryl esters, especially phenyl esterssuitably substituted by electron-attracting substituents (which can beobtained, for example, by treating the corresponding acid with asuitably substituted phenol, for example 4-nitrophenol,4-methylsulfonyl-phenol, 2,4,5-trichlorophenol,2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of acondensation agent, such as N,N'-dicyclohexylcarbodiimide; activatedaryl esters method), cyanomethyl esters (which can be obtained, forexample, by treating the corresponding acid with chloroacetonitrile inthe presence of a base; cyanomethyl esters method), thio esters,especially unsubstituted or substituted, for example nitro-substituted,phenylthio esters (which can be obtained, for example, by treating thecorresponding acid with unsubstituted or substituted, for examplenitro-substituted, thiophenols, inter alia by the anhydride orcarbodiimide method; activated thiol esters method), amino or amidoesters (which can be obtained, for example, by treating thecorresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound,for example N-hydroxy-succinimide, N-hydroxy-piperidine,N-hydroxyphthalimide or 1-hydroxy-benzotriazole, for example by theanhydride or carbodiimide method; activated N-hydroxy esters method) orsilyl esters (which can be obtained, for example, by treating thecorresponding acid with a silylating agent, for examplehexamethyldisilazane, and which react readily with hydroxy groups butnot with amino groups).

Anhydrides of an acid of formula IX may be symmetric or preferably mixedanhydrides of those acids, for example anhydrides with inorganic acids,such as acid halides, especially acid chlorides (which can be obtained,for example, by treating the corresponding acid with thionyl chloride,phosphorus pentachloride or oxalyl chloride; acid chloride method),azides (which can be obtained, for example, from a corresponding acidester by way of the corresponding hydrazide and treatment thereof withnitrous acid; azide method), anhydrides with carbonic acidsemi-derivatives, such as with corresponding esters, for examplecarbonic acid lower alkyl semiesters (which can be obtained, forexample, by treating the corresponding acid with haloformic acid loweralkyl esters, such as chloroformic acid lower alkyl esters, or with a1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixedO-alkylcarbonic acid anhydrides method), or anhydrides withdihalogenated, especially dichlorinated, phosphoric acid (which can beobtained, for example, by treating the corresponding acid withphosphorus oxychloride; phosphorus oxychloride method), or anhydrideswith organic acids, such as mixed anhydrides with organic carboxylicacids (which can be obtained, for example, by treating the correspondingacid with an unsubstituted or substituted lower alkane- orphenylalkane-carboxylic acid halide, for example phenylacetic acidchloride, pivalic acid chloride or trifluoroacetic acid chloride; mixedcarboxylic acid anhydrides method) or with organic sulfonic acids (whichcan be obtained, for example, by treating a salt, such as an alkalimetal salt, of the corresponding acid with a suitable organic sulfonicacid halide, such as a lower alkane- or aryl-sulfonic acid chloride, forexample methane- or p-toluene-sulfonic acid chloride; mixed sulfonicacid anhydrides method) and symmetric anhydrides (which can be obtained,for example, by condensing the corresponding acid in the presence of acarbodiimide or 1-diethylaminopropyne; symmetric anhydrides method).

Suitable cyclic amides are especially amides having five-membereddiazacycles of aromatic character, such as amides with imidazoles, forexample imidazole (which can be obtained, for example, by treating thecorresponding acid with N,N'-carbonyldiimidazole; imidazolide method),or pyrazoles, for example 3,5-dimethylpyrazole (which can be obtained,for example, by way of the acid hydrazide by treatment withacetylacetone; pyrazolide method).

Derivatives of acids of formula IX that are used as acylating agents canalso be formed in situ. For example, N,N'-di-substituted amidino esterscan be formed in situ by reacting a mixture of the starting material offormula X and the acid used as acylating agent in the presence of asuitable N,N-di-substituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide. In addition, amino or amido esters of theacids used as acylating agents can be formed in the presence of thestarting material of formula X to be acylated, by reacting a mixture ofthe corresponding acid and amino starting materials in the presence ofan N,N'-di-substituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide, and of an N-hydroxy-amine orN-hydroxy-amide, for example N-hydroxysuccinimide, where appropriate inthe presence of a suitable base, for example 4-dimethylaminopyridine.

The reaction is preferably carried out by reacting a reactive carboxylicacid derivative of a compound of formula IX with a compound of formulaX, the amino group participating in the reaction being in protectedform. In a preferred form of the reaction, a solution of the startingmaterial of formula IX in dimethylformamide is stirred together withN-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride andN-hydroxysuccinimide for a few hours at room temperature, and thereaction mixture so obtained is then added dropwise to a solution of theamine of formula X in dimethylformamide.

The reaction can be carried out in a manner known per se, the reactionconditions depending especially upon whether and how the carboxy groupof the acylating agent has been activated, generally in the presence ofa suitable solvent or diluent or a mixture thereof, and, if necessary,in the presence of a condensation agent which, for example when thecarboxy group participating in the reaction is in the form of ananhydride, may also be an acid-binding agent, with cooling or heating,for example in a temperature range of from approximately -30° C. toapproximately +150° C., especially approximately from 0° C. to +100° C.,preferably from room temperature (approximately +20° C.) to +70° C., inan open or closed reaction vessel and/or in the atmosphere of an inertgas, for example nitrogen. Customary condensation agents are, forexample, carbodiimides, for example N,N'-diethyl-, N,N'-dipropyl-,N,N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide,suitable carbonyl compounds, for example carbonyldiimidazole, or1,2-oxazolium compounds, for example2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.Customary acid-binding condensation agents are, for example, alkalimetal carbonates or hydrogen carbonates, for example sodium or potassiumcarbonate or hydrogen carbonate (customarily together with a sulfate),or organic bases, such as customarily pyridine or sterically hinderedtri-lower alkylamines, for example N,N-diisopropyl-N-ethylamine.

The starting material of formula IX is obtained, for example, byhydrolysis of the corresponding 3-cyano-pyridyl compound. The hydrolysisof cyano to carboxy is carried out in a suitable solvent, such as analcohol, such as ethanol, for example in the presence of a suitablebase, such as aqueous sodium hydroxide solution, at temperatures of fromroom temperature to +150° C., for example at 60° C. The 3-cyano-pyridylcompound is obtained from the corresponding N-oxido-pyridyl compound.For that purpose, the N-oxido group is first converted into a leavinggroup, for example by reaction with a suitable reactive carboxylic acidderivative or sulfonic acid derivative, for example with a suitablelower alkanoic acid chloride, lower alkanoic acid anhydride, such asacetic anhydride, N,N-di-methyl-carbamoyl chloride, toluenesulfonylchloride, methanesulfonyl chloride or tri-fluoromethanesulfonylchloride. The cyano group is then introduced with a suitable nucleophilewhich acts in the ortho-position with respect to the pyridine nitrogen.A nucleophile that introduces cyano is, for example, a suitable silylcyanide, such as tri-lower alkyl-silyl cyanide, for exampletrimethylsilyl cyanide. The introduction of cyano is carried out in asuitable solvent, such as acetonitrile, at temperatures of approximatelyfrom 0° C. to 150° C., preferably approximately from room temperature to100° C.

The N-oxido-pyridyl compound is obtained by oxidising a correspondingpyridyl compound with a suitable oxidising agent, such as a suitableperacid, for example a suitable perbenzoic acid, such as especiallym-chloro-perbenzoic acid, in an inert solvent, such as methylenechloride, at room temperature.

Process d:

Process d is carried out analogously to Process b.

Process e:

Process e is carried out analogously to Process c. For example, acompound of formula XI can be esterified in the presence of a strongacid, such as concentrated sulfuric acid, the latter actingsimultaneously as an agent binding the elements of water, with thedesired alcohol R₃ --OH, which may serve simultaneously as solvent.Alternatively, a reactive carboxylic acid derivative of a compound offormula XI, for example a suitable ester, such as a methyl ester, can beamidated with an amine of the formula H₂ N--(CH₂)_(n) --R₄ ^(a) or H₂N--(CH₂)_(n) --N(R₃)--R₄.

Acid addition salts of compounds of formula I are obtained in customarymanner, for example by treatment with an acid or a suitable anionexchange reagent.

Acid addition salts can be converted in customary manner into the freecompounds, for example by treatment with a suitable basic agent.

Mixtures of isomers can be separated into the individual isomers in amanner known per se, for example by fractional crystallisation,chromatography, etc.

The processes described above, including the processes for removingprotecting groups and the additional process measures are, unlessotherwise indicated, carried out in a manner known per se, for examplein the presence or absence of preferably inert solvents or diluents, ifnecessary in the presence of condensation agents or catalysts, atreduced or elevated temperature, for example in a temperature range offrom approximately -20° C. to approximately 150° C., especially fromapproximately 0° C. to approximately +70° C., preferably fromapproximately +10° C. to approximately +50° C., principally at roomtemperature, in a suitable vessel and, if necessary, in an inert gasatmosphere, for example a nitrogen atmosphere.

Taking into account all the substituents in the molecule, if necessary,for example if readily hydrolysable radicals are present, especiallymild reaction conditions are to be used, such as short reaction times,the use of mild acidic or basic agents in low concentration,stoichiometric ratios, and the selection of suitable catalysts,solvents, temperature conditions and/or pressure conditions.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining process steps are carried out orthe process is discontinued at any stage or a starting material isformed under the reaction conditions or is used in the form of areactive derivative or salt. The starting materials used are preferablythose which, according to the process, result in the compounds describedabove as being especially valuable.

The invention relates preferably to processes for the preparation of acompound of formula Ia ##STR15## wherein R₁ is

a) N-(amino-lower alkyl)-carbamoyl,

b) N-(hydroxy-lower alkyl)-carbamoyl,

c) hydrazino,

d) cyclohexyl-amino that is unsubstituted or substituted by amino, or

e) lower alkylamino that is substituted by cyano, imidazolyl, guanidyl,amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino,di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl,carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy,dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl,formylpiperazinyl, prolylamido or by a radical of the formula H₂N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl,hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl,indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl,carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl,4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and

R₂ is C₁ -C₆ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine,trifluoromethyl, hydroxy, phenyl, amino, mono(C₁ -C₃ alkyl)amino, di(C₁-C₃ alkyl)amino, C₂ -C₄ alkanoyl, propenyloxy, carboxy, carboxy-methoxy,ethoxycarbonyl-methoxy, sulfanilamido, N,N-di(C₁ -C₃alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl,1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl,cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formulae:

--CO₂ R₃, --NH--C(═O)--R₃, --N(R₃)--C(═O)--R₄, --O--(CH₂)_(n)--N(R₃)--R₄, --C(═O)--NH--(CH₂)_(n) --N(R₃)--R₄, --CH(CH₃)--NH--CHO,--C(CH₃)═N--OH, --C(CH₃)═N--O--CH₃, --CH(CH₃)--NH₂, --NH--CH₂--C(═O)--N(R₃)--R₄, ##STR16## wherein R₃ arid R₄ are each independentlyof the other C₁ -C₃ alkyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2or 3, R₅ is hydrogen, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, chlorine, brominiodine or trifluoromethyl, R₆ is 1H-imidazol-1-yl or morpholinyl, and R₇is C₁ -C₃ alkyl or is phenyl that is unsubstituted or mono-substitutedby C₁ -C₃ alkyl, halogen or by trifluoromethyl, or a salt thereof,wherein

a) a compound of formula II ##STR17## wherein R₈ and R₉ am eachindependently of the other lower alkyl and R₁ is as defined above,functional groups present in a compound of formula II, with theexception of the groups participating in the reaction, being, ifnecessary, in protected form, or a salt of such a compound is reactedwith a compound of formula IIIa ##STR18## wherein R₂ is as definedabove, functional groups present in a compound of formula IIIa, with theexception of the guanidino group participating in the reaction, being,if necessary, in protected form, or with a salt of such a compound, andany protecting groups present are removed, or

b) for the preparation of a compound of formula Ia wherein R₁ has anyone of the above-mentioned meanings c) to e) and R₂ has any one of theabove-mentioned meanings, a compound of formula IVa ##STR19## wherein Yis a leaving group and R₂ is as defined above, functional groups presentin a compound of formula IVa, with the exception of the leaving groupparticipating in the reaction, being, if necessary, in protected form,or a salt of such a compound is reacted with an amine of the formula

    H.sub.2 N--R.sub.12                                        (V)

wherein R₁₂ is amino or unsubstituted or amino-substituted cyclohexyl,or is lower alkyl that is substituted by cyano, imidazolyl, guanidyl,amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino,di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl,carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy,dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl,formylpiperazinyl, prolylamido or by a radical of the formula H₂N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl,hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl,indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl,carbamoyl-methyl, 2-carbamoylethyl, carboxy-methyl, 2-carboxy-ethyl,4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl,functional groups present in R₁₂ being, if necessary, in protected form,and any protecting groups present are removed, or

c) for the preparation of a compound of formula Ia wherein R₁ isN-(amino-lower alkyl)-carbamoyl or N-(hydroxy-lower alkyl)-carbamoyl andR₂ has any one of the above-mentioned meanings, a carboxylic acid offormula IXa ##STR20## wherein R₂ has any one of the above-mentionedmeanings, or a reactive acid derivative thereof is reacted with an amineof formula X

    H.sub.2 N--R.sub.13                                        (X),

wherein R₁₃ is amino-lower alkyl or hydroxy-lower alkyl, the amino orhydroxy group being, if necessary, in protected form, and any protectinggroups present are removed, and, if desired, a compound of formula Iobtained in accordance with any one of Processes a-c is convened intoits salt or an obtained salt of a compound of formula I is convened intothe free compound.

The present invention relates also to novel starting materials and/orintermediates and to processes for the preparation thereof. The startingmaterials used and the reaction conditions chosen are preferably suchthat the compounds described in this Application as being especiallypreferred are obtained.

The invention relates also to a method of treating warm-blooded animalssuffering from a tumour disease, which method comprises administering towarm-blooded animals requiring such treatment an amount that iseffective in inhibiting tumours of a compound of formula I or of apharmaceutically acceptable salt thereof. The invention relates also tothe use of a compound of formula I or of a pharmaceutically acceptablesalt thereof in the inhibition of protein kinase C in warm-bloodedanimals or in the preparation of pharmaceutical compositions for use inthe therapeutic treatment of the human or animal body. Depending on thespecies, age, individual condition, mode of administration and theparticular clinical picture, effective doses, for example daily doses ofapproximately 1-1000 mg, especially 50-500 mg, are administered to awarm-blooded animal of approximately 70 kg body weight.

The invention relates also to pharmaceutical compositions comprising aneffective amount, especially an amount effective in the prophylaxis ortreatment of one of the above-mentioned disorders, of the activeingredient together with pharmaceutically acceptable carriers that aresuitable for topical, enteral, for example oral or rectal, or parenteraladministration and that may be inorganic or organic, solid or liquid.There are used for oral administration especially tablets or gelatincapsules that comprise the active ingredient together with diluents, forexample lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/orglycerol, and/or lubricants, for example silica, talc, stearic acid orsalts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol. Tablets may also comprise binders, for examplemagnesium aluminium silicate, starches, such as corn, wheat or ricestarch, gelatin, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrators, for examplestarches, agar, alginic acid or a salt thereof, such as sodium alginate,and/or effervescent mixtures, or adsorbents, dyes, flavourings andsweeteners. It is also possible to use the pharmacologically activecompounds of the present invention in the form of parenterallyadministrable compositions or in the form of infusion solutions. Suchsolutions are preferably isotonic aqueous solutions or suspensionswhich, for example in the case of lyophilised compositions that comprisethe active ingredient alone or together with a carrier, for examplemannitol, can be made up prior to use. The pharmaceutical compositionsmay be sterilised and/or may comprise excipients, for examplepreservatives, stabilisers, wetting agents and/or emulsifiers,solubilisers, salts for regulating the osmotic pressure and/or buffers.The present pharmaceutical compositions, which may, if desired, compriseother pharmacologically active substances, such as antibiotics, areprepared in a manner known per se, for example by means of conventionalmixing, granulating, confectioning, dissolving or lyophilisingprocesses, and comprise approximately from 1% to 100%, especially fromapproximately 1% to approximately 20%, active ingredient(s).

The following Examples illustrate the invention without limiting it inany way. The R_(f) values are determined on silica gel thin-layer plates(Merck, Darmstadt, Germany). The ratio of the eluants in the eluantmixtures used is indicated in parts by volume (v/v) and temperatures areindicated in degrees Celsius.

Abbreviations:

conc.: concentrated

HV: high vacuum

RF: reflux

RT: room temperature

h: hour(s)

The abbreviations in respect of NMR spectra have the following meanings:

br: broad

d: doublet

H: hydrogen

m: multiplet

s: singlet

EXAMPLE 1

50 mg (0.143 mmol) ofN-(3-trifluoromethyl-phenyl)-4-(2-chloro4-pyridyl)-2-pyrimidineamine arestirred for 44 h at 100° in 1 ml of 3-amino-1-propanol. Concentration byevaporation and chromatography (methylene chloride:methanol=9:1) giveN-(3-trifluoromethyl-phenyl)-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine; R_(f) =0.1(methylene chloride:methanol=95:5), FAB-MS: 390, m.p. 158°-163°.

The starting material is obtained in the following manner:

Stage 1.1: 24.61 g (177.62 mmol) of 2-chloro-4-cyano-pyridine are placedin 1.25 litres of diethyl ether under nitrogen, and 120 ml (22% intetrahydrofuran, 353 mmol) of methyl-magnesium chloride are added. Thered suspension is stirred for 40 h at RT, poured onto 1.25 litres ofice/water and 250 ml of 6N HCl and stirred for 14 h at RT. Extractionwith diethyl ether and methylene chloride, drying with MgSO₄ andconcentration give 4-acetyl-2-chloro-pyridine; R_(f) =0.5 (methylenechloride:methanol=9:1).

Alternatively, 4-acetyl-2-chloro-pyridine can be obtained in thefollowing manner:

5.0 g (36.5 mmol) of 4-acetyl-pyridine N-oxide and 6.64 ml (73 mmol) ofphosphorus oxychloride are stirred in 50 ml of toluene for 2 h at 100°.The reaction mixture is stirred at 50° into 500 ml of 10N sodiumhydroxide solution, extracted with ethyl acetate and treated with Tonsil(Fluka; bentonite--colloidal aqueous aluminium silicate). Concentrationand crystallisation (diethyl ether/n-hexane) give4-acetyl-2-chloro-pyridine;

m.p. 35°, FAB-MS: 156 (M⁺ +H).

The 4-acetyl-pyridine N-oxide used is prepared in the following manner:11.0 ml (100 mmol) of 4-acetyl-pyridine and 31.3 g (100 mmol) of 55%m-chloro-perbenzoic acid are boiled under RF for 16 h in 200 ml ofmethylene chloride. Precipitation with 200 ml of diethyl ether gives4-acetyl-pyridine N-oxide; m.p. 132°-133°.

Stage 1.2: 16.2 g (104.2 mmol) of 4-acetyl-2-chloro-pyridine are stirredat 110° with 116 ml of dimethylformamide diethylacetal for 1 h. Coolingto 0°, filtering and drying at 60° under HV give3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one; ¹ H-NMR (dimethylsulfoxide): 2.98 (3H,s), 3.2 (3H,s), 5.9 (1H,d), 7.8 (3H,m), 8.5 (1H

Stage 1.3: 6.3 g (150 mmol) of cyanamide (50% in water) are added to asuspension of 16.1 g (100 mmol) of 3-trifluoromethyl-aniline in 35 ml ofethanol. 7.0 ml of nitric acid (65%, 0.1 mol) are then added to thebrown solution and the reaction mixture is heated for 20 h under RF. Itis then cooled to 0° and filtered, and the material retained on thefilter is washed with ethanol and dried at 60° under HV to give3-trifluoromethyl-phenylguanidine nitrate; ¹ H-NMR (dimethyl sulfoxide):7.6 (7H,m), 9.9 (1H,br,s).

Stage 1.4: 150 mg (0.71 mmol) of3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one are suspended in1.5 ml of 2-propanol. 190 mg (0.712 mmol) of3-trifluoromethylphenyl-guanidine nitrate and 31 mg (0.783 mmol) ofsodium hydroxide are added and the reaction mixture is stirred for 18 hunder RF. It is then cooled to RT and filtered, and the materialretained on the filter is washed with 2-propanol and water and dried at50° under HV to giveN-(3-trifluoromethyl-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine;

m.p. 169°-171°, R_(f) =0.67 (methylene chloride:methanol=95:5), FAB-MS:351 (M⁺ +H).

EXAMPLE 2

Analogously to Example 1, there is obtained from 20 mg (0.063 mmol) ofN-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 1 ml of3-amino-1-propanol N-(3-chloro-phenyl)-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine;

m.p. 144°-147°, R_(f) =0.12 (methylene chloride:methanol=95:5), FAB-MS:356 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 2.1: Analogously to Stage 1.4, there is obtained from 150 mg (0.7mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 165mg (0.71 mmol) of 3-chloro-phenyl-guanidine nitrateN-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine;

m.p. 196°-198°, R_(f) =0.7 (methylene chloride:methanol=95:5).

Alternatively,N-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine can beobtained in the following manner:

10.0 g (32 mmol) ofN-(3-chloro-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine are stirredfor 24 h in 100 ml of phosphorus oxychloride at 110°. The reactionmixture is stirred at 50° into 2N sodium hydroxide solution andextracted with tetrahydrofuran. Concentration and crystallisation(tetrahydrofuran/ethanol) of the residue giveN-(3-chloro-phenyl)-4-(2-chloro4-pyridyl)-2-pyrimidineamine; m.p.196°-198°, R_(f) =0.7 (methylene chloride:methanol=95:5).

The N-(3-chloro-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine used isprepared in the following manner:

10 g (35.4 mmol) of N-(3-chloro-phenyl)-4-(4-pyridyl)-2-pyrimidineamineand 11.1 g (35.4 mmol) of m-chloroperbenzoic acid are stirred for 5 h atRT in 500 ml of methylene chloride. Concentration and crystallisation(acetic acid) of the residue giveN-(3-chloro-phenyl)-4-(N-oxido4-pyridyl)-2-pyrimidineamine; m.p.274°-275°, R_(f) =0.6 (methylene chloride:methanol=9:1).

Stage 2.2: Analogously to Stage 1.3, there is obtained from 4.1 ml (0.04mol) of 3-chloroaniline and 3.3 g (0.078 mol) of cyanamide (50% inwater) 3-chloro-phenyl-guanidine nitrate; ¹ H-NMR (dimethyl sulfoxide):7.2-7.7 (7H,m), 9.5 (1H,br,s).

EXAMPLE 3

The following compounds are prepared in a manner analogous to thatdescribed above and by simple conversion reactions, known per se, of theproducts:

a) N-(3-chloro-phenyl)-4-2-(2-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine,

b) N-(3-chloro-phenyl)-4-2-(2-carboxy-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

c) N-(3-phenyl)-4-2-(2-carbamoyl-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

d) N-(3-chloro-phenyl)-4-2-(2-ethoxycarbonylethylamino)-4-pyridyl!-2-pyrimidineamine,

e) N-(3-trifluoromethyl-phenyl)-4-2-(2-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine,

f) N-(3-trifluoromethyl-phenyl)-4-2-(2-carboxy-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

g) N-(3-trifluoromethyl-phenyl)-4-2-(2-carbamoyl-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

h) N-(3-trifluoromethyl-phenyl)-4-2-(2-ethoxycarbonyl-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

i) N-(3-chloro-phenyl)-4-2-(2-imidazol-1-ylethyl-amino)-4-pyridyl!-2-pyrimidineamine,

j) N-(3-chloro-phenyl)-4-2-(2-acetamido-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

k) N-(3-chloro-phenyl)-4-(2-hydrazino-4-pyridyl)-2-pyrimidineamine,

l) N-(3-chloro-phenyl)-4-2-(2-guanidyl-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

m) N-(3-chloro-phenyl)-4-2-{2-(methylamino-carbonylamino)-ethyl-amino}-4-pyridyl!-2-pyrimidineamine,

n) N-(3-chloro-phenyl)-4-2-(2-amidino-ethyl-amino)-4-pyridyl!-2-pyrimiclineamine,

o) N-(3-chloro-phenyl)-4-2-(2-glycylamino-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

p) N-(3-chloro-phenyl)-4-2-(N-{2-amino-ethyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine (seealso Example 6),

q) N-(3-chloro-phenyl)-4-2-(N-{2-hydroxy-ethyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine (seealso Example 7),

r) N-(3-chloro-phenyl)-4-2-(N-{3-amino-prop-1-yl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine(see also Example 9),

s) N-(3-chloro-phenyl)-4-2-(N-{3-hydroxy-propyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine (seealso Example 8),

t) N-(3-chloro-phenyl)-4-2-{2-(N-hydroxy-carbamoyl)-ethyl-amino}-4-pyridyl!-2-pyrimidineamine,

u) N-(3-chloro-phenyl)-4-2-{3-(N-hydroxy-carbamoyl)-propyl-amino}-4-pyridyl!-2-pyrimidineamine,

v) N-(3-chloro-phenyl)-4-2-{2-(dihydroxy-phosphoryloxy)-ethyl-amino}4-pyridyl!-2-pyrimidineamine,

w) N-(3-chloro-phenyl)-4-2-{3-(dihydroxy-phosphoryloxy)-propyl-amino}-4-pyridyl!-2-pyrimidineamine,

x) N-(3-trifluoromethyl-phenyl)-4-2-(2-{N-hydroxy-carbamoyl}-ethyl-amino)-4-pyridyl!-2-pyrimidineamine,

y) N-(3-trifluoromethyl-phenyl)-4-2-(3-{N-hydroxy-carbamoyl}-propyl-amino)-4-pyridyl!-2-pyrimidineamine,

z) N-(3-trifluoromethyl-phenyl)-4-2-(2-{dihydroxy-phosphoryl-oxy}-ethyl-amino)-4-pyridyl!-2-pyrimidineamineand

zα) N-(3-trifluoromethyl-phenyl)-4-2-(3-{dihydroxy-phosphoryl-oxy}-propyl-amino)-4-pyridyl!-2-pyrimidineamine.

EXAMPLE 4

20 mg (0.063 mmol) ofN-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine are stirredfor 26 h at 110° with 1 ml of ethylenediamine. Concentration andchromatography (methylene chloride:methanol:conc. ammoniasolution=80:20: 1) give N-(3-chloro-phenyl)-4-2-(2-amino-ethyl-amino)-4-pyridyl!-2-pyrimidineamine; R_(f) =0.15(methylene chloride:methanol:conc. ammonia solution=80:20:1), FAB-MS:341 (M⁺ +1).

EXAMPLE 5

Analogously to Example 4, there is obtained from 50 mg (0.157 mmol) ofN-(3-trifluoromethyl-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 1 ml of ethylenediamine N-(3-trifluoromethyl-phenyl)-4-2-(2-amino-ethyl-amino)-4-pyridyl!-2-pyrimidineamine; R_(f) =0.15(methylene chloride:methanol:conc. ammonia solution=80:20: 1), FAB-MS:375 (M⁺ +H).

EXAMPLE 6

80 mg (0.24 mmol) of N-3-chloro-phenyl!-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 70.8 mg(0.36 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimidehydrochloride and 42 mg (0.36 mmol) of N-hydroxysuccinimide aredissolved in 3 ml of dimethylformamide and stirred for 2.5 h at RT. Thereaction mixture is then added dropwise at 0° within a period of 30minutes to a solution of 0.77 ml (11.8 mmol) of ethylenediamine in 2 mlof DMF. After stirring for 14 h at RT, the reaction mixture is pouredinto 50 ml of ethyl acetate and extracted with 30 ml of water. Theorganic phase is dried (sodium sulfate) and concentrated.Crystallisation from isopropanol/ethanolic hydrochloric acid gives N-3-chloro-phenyl!-4-2-(N-{2-amino-ethyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineaminehydrochloride; m.p. 161°-163°, FAB-MS: 369 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 6.1: 50 mg (0.16 mmol) ofN-(3-chloro-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine are stirredin 5 ml of ethanol and 5 ml of 2N sodium hydroxide solution for 2 h at60°. After cooling to RT and filtering, the material retained on thefilter is washed with ethanol/water (9:1) and dried at 50° under HV togive the sodium salt ofN-(3-chloro-phenyl)-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine;m.p. >250°, R_(f) =<0.1 (methylene chloride:methanol=9:1).

EXAMPLE 7

Analogously to Example 6, them is obtained from 100 mg (0.3 mmol) of N-3-chloro-phenyl!-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 88.5 mg(0.46 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimidehydrochloride, 53 mg (0.46 mmol) of N-hydroxysuccinimide and 0.9 ml (14mmol) of ethanolamine N- 3-chloro-phenyl!-4-2-(N-{2-hydroxy-ethyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine; m.p.206°, FAB-MS: 370 (M⁺ +H).

EXAMPLE 8

Analogously to Example 6, there is obtained from 80 mg (0.24 mmol) of N-3-chloro-phenyl!-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 70 mg (0.36mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride,42 mg (0.36 mmol) of N-hydroxysuccinimide and 0.7 ml (11.8 mmol) ofaminopropanol N- 3-chloro-phenyl!-4-2-(N-{3-hydroxy-propyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine;

m.p. 152°-153°, FAB-MS: 384 (M⁺ +H).

EXAMPLE 9

Analogously to Example 6, there is obtained from 50 mg (0.15 mmol) of N-3-chloro-phenyl!-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 44 mg (0.22mmol) of N-ethyl--N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride,26 mg (0.22 mmol) of N-hydroxysuccinimide and 0.48 ml (7.3 mmol) ofdiaminopropane N- 3-chloro-phenyl!-4-2-(N-{3-amino-prop-1-yl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineaminehydrochloride; m.p. 173°-178°, FAB-MS: 383 (M⁺ +H).

EXAMPLE 10

Analogously to Example 1, there is obtained from 500 mg (1.5 mmol) of N-3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 1 ml (16.3mmol) of aminoethanol N- 3-chloro-phenyl!-4-2-(2-hydroxy-ethyl-amino)-4-pyridyl!-2-pyrimidineamine;

m.p. 180°-181°, FAB-MS: 342 (M⁺ +H).

EXAMPLE 11

Analogously to Example 1, there is obtained from 6.4 g (19.6 mmol) of N-3-carboxy-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 12 ml(160 mmol) of 3-aminopropanol, after crystallisation from ethanol/1Nhydrochloric acid, N- 3-carboxy-phenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine;

m.p. 258°-259°, FAB-MS: 366 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 11.1: Analogously to Stage 1.3, there is obtained from 24.4 g (148mmol) of amino-benzoic acid ethyl ester, 10.25 ml (150 mmol) of 65%nitric acid and 9.66 g (230 mmol) of 98% cyanamide3-ethoxycarbonyl-phenyl-guanidine nitrate; ¹ H-NMR (DMSO, D₂ O): 1.3(t,3H), 4.3 (q,2H), 7.4-7.9 (m,4H).

Stage 11.2: Analogously to Stage 1.4, there is obtained from 14.5 g(53.7 mmol) of 3-ethoxycarbonyl-phenyl-guanidine nitrate, 11.3 g (53.7mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 2.4 g(60 mmol) of sodium hydroxide N-3-ethoxy-carbonyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine; m.p.149°-150°, FAB-MS: 355 (M⁺ +H).

Stage 11.3: 9.4 g (26.5 mmol) of N-3-ethoxycarbonyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 50ml of 2N sodium hydroxide solution are boiled under RF in 300 ml ofethanol for 1 h. After cooling to RT, the reaction mixture is acidified(4N hydrochloric acid) and filtered. After drying at 50° under HV,lemon-yellow crystals of N-3-carboxy-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine are obtained;m.p. 267°-268°, FAB-MS: 327 (M⁺ +H).

EXAMPLE 12

2.0 g (5.4 mmol) of N-3-carboxy-phenyl!-4-(2-(3-hydroxy-propyl-amino)-4-pyridyl)-2-pyrimidineamineand 0.28 ml (5.4 mmol) of conc. sulfuric acid are boiled under RF in 150ml of methanol for 24 h. After cooling to RT, the reaction mixture isconcentrated to half the volume, diluted with 100 ml of ethyl acetateand extracted twice with 50 ml of buffer (pH 7) each time. The organicphase is dried (Na₂ SO₄) and concentrated. Crystallisation (methylenechloride/methanol) gives N- 3-methoxycarbonylphenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine; m.p. 162°-163°,FAB-MS: 380 (M⁺ +H).

EXAMPLE 13

Analogously to Example 1, them is obtained from 300 mg (0.95 mmol) of N-3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 3 ml (32.3mmol) of aminobutanol N- 3-chloro-phenyl!-4-2-(4-hydroxy-butyl-amino)-4-pyridyl!-2-pyrimidineamine;

m.p. 136°-139°, FAB-MS: 370 (M⁺ +H).

EXAMPLE 14

Analogously to Example 1, there is obtained, in the melt, from 50 mg(0.16 mmol) of N-3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 350 mg(3.15 mmol) of histamine, that is to say 2-(imidazol-4-yl)-ethyl-amine,N- 3-chloro-phenyl!-4-{2-2-(imidazol-4-yl)-ethyl-amino!-4-pyridyl}-2-pyrimidineamine;

m.p. 140°-146°, FAB-MS: 392 (M⁺ +H).

EXAMPLE 15

Analogously to Example 1, there is obtained from 1.16 g (3.91 mmol) ofN- 3-methyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 23 ml(304.9 mmol) of 3-aminopropanol N- 3-methyl-phenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine; m.p. 138°-139°,FAB-MS: 336 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 15.1: Analogously to Stage 1.3, there is obtained from 2.02 ml(18.7 mmol) of m-toluidine, 1.95 ml (29.9 mmol) of conc. hydrochloricacid and 0.89 g (37.3 mmol) of 98% cyanamide, after precipitation with0.47 g (37.3 mmol) of ammonium nitrate, 3-methyl-phenyl-guanidinenitrate; ¹ H-NMR (DMSO): 2.3 (s,3H), 7.0-7.5 (m,8H), 9.5 (br, s, 1H).

Stage 15.2: Analogously to Stage 1.4, there is obtained from 1.09 g(5.17 mmol) of 3-methyl-phenyl-guanidine nitrate, 1.09 g (5.17 mmol) of3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 0.23 g (5.68mmol) of sodium hydroxide N-3-methyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine; ¹ H-NMR(DMSO): 2.3 (s,3H), 6.8 (d,1H), 7.2 (t, 1H), 7.6 (m,2H), 7.7 (s, 1H),8.1 (m,1H), 8.2 (s, 1H), 8.6 (d, 1H), 8.7 (d,1H), 9.8 (s, 1H).

EXAMPLE 16

Analogously to Example 1, there is obtained from 168.8 mg (0.53 mmol) ofN- 3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 113.2mg (1.06 mmol) of 5-aminopentanol N- 3-chloro-phenyl!-4-2-(5-hydroxy-pentyl-amino)-4-pyridyl!-2-pyrimidineamine; FAB-MS: 384 (M⁺+H), 298.

EXAMPLE 17

500 mg (1.4 mmol) of N-3-ethoxycarbonyl-phenyl!4-(2-chloro-4-pyridyl)-2-pyrimidineamine arestirred in 1 ml of 3-aminopropanol for 15 h at 140°. Chromatography(silica gel, methylene chloride:methanol=9:1) gives N-3-{N-(3-hydroxy-propyl)-amino-carbonyl}-phenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine;

m.p. 153°-154°, FAB-MS: 423 (M⁺ +H).

EXAMPLE 18

100 mg (0.26 mmol) of N- 3-methoxycarbonyl-phenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine and 0.5 ml of1,3-diamino-propane are stirred for 24 h at 90° and then diluted with 20ml of ethyl acetate and extracted with 2×10 ml of sodium chloridesolution. The organic phase is dried, concentrated and crystallised frommethylene chloride/diethyl ether to give N-3-{N-(3-amino-propyl)-aminocarbonyl}-phenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine;

m.p. 169°-170°, FAB-MS: 422 (M⁺ +H).

EXAMPLE 19

Analogously to Example 18, there is obtained from 100 mg (0.26 mmol) ofN- 3-methoxycarbonyl-phenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine and 150 mg (1.35mmol) of histamine, that is to say 2-(imidazol-4-yl)-ethyl-amine, N-3-{N-(2-imidazol-4-yl-ethyl)-aminocarbonyl}-phenyl!-4-2-(3-hydroxy-propylamino)-4-pyridyl!-2-pyrimidineamine; m.p. 181°-186°,FAB-MS: 459 (M⁺ +H).

EXAMPLE 20

Analogously to Example 1, there is obtained from 300 mg (0.9 mmol) of N-3-chloro-6-methyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and5.3 ml (70.65 mmol) of 3-aminopropanol N- 3-chloro-6-methyl-phenyl!-4-2-(3-hydroxy-propylamino)-4-pyridyl!-2-pyrimidineamine; m.p. 117°-119°,FAB-MS: 370 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 20.1: Analogously to Stage 1.3, there is obtained from 10.0 g(60.62 mmol) of 5-chloro-2-methyl-aniline, 9.45 ml (113 mmol) of conc.hydrochloric acid and 5.94 g (141.2 mmol) of 98% cyanamide, afterprecipitation with 11.3 g (141.2 mmol) of ammonium nitrate,5-chloro-2-methyl-phenyl-guanidine nitrate; ¹ H--NMR (DMSO): 2.2 (s,3H),7.2-7.4 (m,7H).

Stage 20.2: Analogously to Stage 1.4, there is obtained from 1.75 g(7.12 mmol) of 3-chloro-6-methyl-phenyl-guanidine nitrate, 1.5 g (7.12mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 0.31g (7.83 mmol) of sodium hydroxide N-3-chloro-6-methyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine; ¹H-NMR (DMSO): 2.2 (s,3H), 7.1 (d×d, 1H), 73 (d,1H), 7.6 (d, 1H), 7.8 (d,1H), 8.05 (d×d, 1H), 8.15 (s, 1H), 8.6 (m,2H), 9.2 (s, 1H).

EXAMPLE 21

Analogously to Example 1, there is obtained from 300 mg (0.85 mmol) ofN- 3,6-dichloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 5.0ml (66.55 mmol) of 3-aminopropanol N- 3,6-dichloro-phenyl!-4-2-(3-hydroxy-propylamino)-4-pyridyl!-2-pyrimidineamine; m.p. 130°-132°,FAB-MS: 390 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 21.1: Analogously to Stage 1.3, there is obtained from 10.0 g(61.72 mmol) of 2,5-dichloro-aniline, 8.25 ml (98.7 mmol) of conc.hydrochloric acid and 5.19 g (123.4 mmol) of 98% cyanamide, afterprecipitation with 9.88 g (123.4 mmol) of ammonium nitrate,2,5-dichloro-phenyl-guanidine nitrate; ¹ H-NMR (DMSO): 7.4-7.7 (m,7H).

Stage 21.2: Analogously to Stage 1.4, there is obtained from 1.9 g (7.12mmol) of 3,6-dichloro-phenyl-guanidine nitrate, 1.5 g (7.12 mmol) of3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 0.31 g (7.83mmol) of sodium hydroxide N-3,6-dichloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine; ¹ H-NMR(DMSO): 7.25 (d×d, 1H), 7.6 (d,1H), 7.7 (d,1 H), 8.05 (m,2H), 8.2(s,1H), 8.6 (d,1H), 8.7 (d, 1H), 9.25 (s, 1H).

EXAMPLE 22

Analogously to Example 1, there is obtained from 300 mg (0.86 mmol) ofN- 3-chloro-6-methoxy-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 5.1 ml (67.4 mmol) of 3-aminopropanol N-3-chloro-6-methoxy-phenyl!-4-2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine; m.p. 131°-133°,FAB-MS: 386 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 22.1: Analogously to Stage 1.3, there is obtained from 10.0 g(63.45 mmol) of 5-chloro-2-methoxy-aniline, 8.5 ml (101.5 mmol) of conc.hydrochloric acid and 5.3 g (126.9 mmol) of 98% cyanamide, afterprecipitation with 10.2 g (126.9 mmol) of ammonium nitrate,5-chloro-2-methoxy-phenyl-guanidine nitrate; ¹ H-NMR (DMSO): 3.9 (s,3H),7.2-7.4 (m,7H).

Stage 22.2: Analogously to Stage 1.4, there is obtained from 1.87 g(7.12 mmol) of 3-chloro-6-methoxy-phenyl-guanidine nitrate, 1.5 g (7.12mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 0.31g (7.83 mmol) of sodium hydroxide N-3-chloro-6-methoxy-phenyl!4-(2-chloro-4-pyridyl)-2-pyrimidineamine; ¹H-NMR (DMSO): 3.9 (s,3H), 7.1 (d,1H), 7.7 (d,1H), 8.1 (d×d, 1H), 8.2(s,1H), 8.3 (s,1H), 8.5 (s,1H), 8.6 (d1H), 8.75 (d,1H).

EXAMPLE 23

Analogously to Example 1, there is obtained from 100 mg (0.31 mmol) ofN- 3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 500 mg(5.63 mmol) of piperazine, from the melt after chromatography (methylenechloride:methanol=95:5), N- 3-chloro-phenyl!-4-2-(1-piperazinyl)-4-pyridyl!-2-pyrimidineamine;

m.p. 175°-180°, FAB-MS: 367 (M⁺ +H).

EXAMPLE 24

Analogously to Example 1, there is obtained from 100 mg (0.31 mmol) ofN- 3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 1.0 ml(7.5 mmol) of 4-(2-amino-ethyl)-morpholine N- 3-chloro-phenyl!-4-(2-2-{4-morpholinyl}ethyl-amino!-4-pyridyl)-2-pyrimidineamine; m.p.176°-186°, FAB-MS: 411 (M⁺ +H).

EXAMPLE 25

Analogously to Example 1, there is obtained from 100 mg (0.32 mmol) ofN- 3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 1.0 ml(7.4 mmol) of 1-(2-amino-ethyl)-piperazine N- 3-chloro-phenyl!-4-{2-4-(2-amino-ethyl)-piperazin-1-yl)!-4-pyridyl}-2-pyrimidineamine; m.p.250°, FAB-MS: 410 (M⁺ +H).

EXAMPLE 26

Analogously to Example 1, there is obtained from 100 mg (0.32 mmol) ofN- 3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 1.0 ml(8.35 mmol) of 2-(3-amino-propylamino)-ethanol N- 3-chloro-phenyl!-4-{2-3-(2-hydroxy-ethyl-amino)-propylamino!-4-pyridyl}-2-pyrimidineamine;m.p. 143°-150°, FAB-MS: 399 (M⁺ +H).

EXAMPLE 27

Analogously to Example 1, there is unexpectedly obtained from 100 mg(0.315 mmol) of N-3-chloro-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 1.0 ml(9.97 mmol) of 4-amino-morpholine N- 3-chloro-phenyl!-4-2-(4-morpholinyl)-4-pyridyl!-2-pyrimidineamine; m.p. 163°-169°, FAB-MS:368 (M⁺ +H).

EXAMPLE 28

Tablets each comprising 20 mg of active ingredient, for example one ofthe compounds of formula I described in Examples 1-27, are prepared withthe following composition in customary manner:

    ______________________________________                                        Composition:                                                                  ______________________________________                                        active ingredient     20     mg                                               wheat starch          60     mg                                               lactose               50     mg                                               colloidal silica      5      mg                                               talc                  9      mg                                               magnesium stearate    1      mg                                                                     145    mg                                               ______________________________________                                    

Preparation: The active ingredient is mixed with a portion of the wheatstarch, with the lactose and with the colloidal silica, and the mixtureis forced through a sieve. A further portion of the wheat starch is madeinto a paste with 5 times the amount of water on a water bath, and thepowder mixture is kneaded with the paste until a slightly plastic masshas been formed.

The plastic mass is pressed through a sieve of approximately 3 mm meshsize and dried, and the resulting dry granules are forced through asieve again. The remainder of the wheat starch, the talc and themagnesium stearate are admixed and the mixture is compressed to formtablets each weighing 145 mg and having a breaking notch.

EXAMPLE 29

Capsules each comprising 10 mg of active ingredient, for example one ofthe compounds of formula I described in Examples 1-27, are prepared incustomary manner as follows:

    ______________________________________                                        Composition:                                                                  ______________________________________                                        active ingredient     2500   mg                                               talcum                200    mg                                               colloidal silica      50     mg                                               ______________________________________                                    

Preparation: The active ingredient is intimately mixed with the talcumand the colloidal silica, and the mixture is forced through a sieve of0.5 mm mesh size and introduced in 11-mg portions into hard gelatincapsules of suitable size.

What is claimed is:
 1. An N-phenyl-2-pyrimidineamine derivative of formula I ##STR21## wherein R₀ is hydrogen, halogen, lower alkoxy or lower alkyl,R₁ isa) N-(amino-lower alkyl)-carbamoyl, b) N-(hydroxy-lower alkyl)-carbamoyl, c) hydrazino, d) cyclohexyl-amino that is unsubstituted or substituted by amino, e) piperazinyl that is unsubstituted or substituted by amino-lower alkyl, f) morpholinyl, or g) lower alkylamino that is substituted by morpholinyl, hydroxy-lower alkylamino, cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and R₂ is C₁ -C₆ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxy, phenyl, amino, mono(C₁ -C₃ alkyl)amino, di(C₁ -C₃ alkyl)amino, C₂ -C₄ alkanoyl, propen-yloxy, carboxy, carboxy-methoxy, ethoxycarbonyl-methoxy, sulfanilamido, N,N-di-(C₁ -C₃ alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formulae:--CO₂ R₃, --NH--C(═O)--R₃, --N(R₃)--C(═O)--R₄, --O--(CH₂)_(n) --N(R₃)--R₄, --C(═O)--NH--(CH₂)_(n) --R₄ ^(a), --C(═O)--NH--(CH₂)_(n) --N(R₃)--R₄, --CH(CH₃)--NH--CHO, --C(CH₃)═N--OH, --C(CH₃)═N--O--CH₃, --CH(CH₃)--NH₂, --NH--CH₂ --C(═O)--N(R₃)--R₄, ##STR22## wherein R₃ and R₄ are each independently of the other C₁ -C₃ alkyl, R₄ ^(a) is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R₅ is hydrogen, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine or trifluoromethyl, R₆ is 1H-imidazol-1-yl or morpholinyl and R₇ is C₁ -C₃ alkyl or is phenyl that is unsubstituted or mono-substituted by C₁ -C₃ alkyl, halogen or by trifluoromethyl, or a salt thereof.
 2. An N-phenyl-2-pyrimidineamine derivative according to claim 1 of formula Ia ##STR23## wherein R₁ isa) N-(amino-lower alkyl)-carbamoyl, b) N-(hydroxy-lower alkyl)-carbamoyl, c) hydrazino, d) cyclohexyl-amino that is unsubstituted or substituted by amino, or e) lower alkylamino that is substituted by cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical of the formula H₂ N--CH(R--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and R₂ is C₁ -C₆ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxy, phenyl, amino, mono(C₁ -C₃ alkyl)amino, di(C₁ -C₃ alkyl)amino, C₂ -C₄ alkanoyl, prop-enyloxy, carboxy, carboxy-methoxy, ethoxycarbonyl-methoxy, sulfanilamido, N,N-di(C₁ -C₃ alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formulae:--CO₂ R₃, --NH--C(═O)--R₃, --N(R₃)--C(═O)--R₄, --O--(CH₂)_(n) --N(R₃)--R₄, --C(═O)--NH--(CH₂)_(n) --N(R₃)--R₄, --CH(CH₃)--NH--CHO, --C(CH₃)═N--OH, --C(CH₃)═N--O--CH₃, --CH(CH₃)--NH₂, --NH--CH₂ --C(═O)--N(R₃)--R₄, ##STR24## wherein R₃ and R₄ are each independently of the other C₁ -C₃ alkyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R₅ is hydrogen, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine or trifluoromethyl, R₆ is 1H-imidazol-1-yl or morpholinyl and R₇ is C₁ -C₃ alkyl or is phenyl that is unsubstituted or mono-substituted by C₁ -C₃ alkyl, halogen or by trifluoromethyl, or a salt thereof.
 3. A compound according to claim 1 of formula I, whereinR₀ is hydrogen, halogen, lower alkoxy or lower alkyl, R₁ isa) N-(amino-lower alkyl)-carbamoyl, b) N-(hydroxy-lower alkyl)-carbamoyl, c) hydrazino, d) piperazinyl that is unsubstituted or substituted by amino-lower alkyl, e) morpholinyl, or f) lower alkylamino that is substituted by morpholinyl, hydroxy-lower alkylamino, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, dihydroxyphosphoryloxy or by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, and R₂ is chlorine, trifluoromethyl, carboxy, a radical of the formula --CO₂ R₃ wherein R₃ is C₁ -C₃ alkyl, or a radical of the formula --C(═O)--NH--(CH₂) _(n) --R₄ ^(a) wherein n is 2 or 3 and R₄ ^(a) is hydroxy, amino or imidazolyl, or a salt thereof.
 4. A compound according to claim 1 of formula I, whereinR₀ is hydrogen, R₁ isa) N-(amino-lower alkyl)-carbamoyl, b) N-(hydroxy-lower alkyl)-carbamoyl, c) hydrazino or d) lower alkylamino that is substituted by imidazolyl, guanidyl, amino, lower alkanoyl-amino, lower alkylamino-carbonylamino, amidino, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, dihydroxyphosphoryloxy or by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, and R₂ is chlorine or trifluoromethyl, or a salt thereof.
 5. A compound according to claim 1 of formula I, whereinR₀ is hydrogen, chlorine, lower alkyl or lower alkoxy, R₁ is N-(ω-amino-C₂ -C₃ alkyl)-carbamoyl, N-(ω-hydroxy-C₂ -C₃ alkyl)-carbamoyl, hydrazino, 2-hydroxy-propylamino or linear C₂ -C₃ alkylamino that is substituted in the ω-position by morpholinyl, ω-hydroxy-lower alkylamino, imidazolyl, guanidyl, amino, lower alkanoylamino, amidino, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxycarbamoyl, hydroxy or by dihydroxyphosphoryloxy, and R₂ is chlorine, trifluoromethyl, carboxy, a radical of the formula --CO₂ R₃ wherein R₃ is C₁ -C₃ alkyl, or a radical of the formula --C(═O)--NH--(CH₂) _(n) --R₄ ^(a) wherein n is 2 or 3 and R₄ ^(a) is hydroxy, amino or imidazolyl, or a salt thereof.
 6. A compound according to claim 1 of formula I, whereinR₀ is hydrogen, R₁ is N-(ω-amino-C₂ -C₃ alkyl)-carbamoyl, N-(ω-hydroxy-C₂ -C₃ alkyl)-carbamoyl, hydrazino, 2-hydroxy-propylamino or linear C₂ -C₃ alkylamino that is substituted in the ω-position by imidazolyl, guanidyl, amino, lower alkanoylamino, amidino, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy or by dihydroxyphosphoryloxy, and R₂ is chlorine or trifluoromethyl, or a salt thereof.
 7. A compound according to claim 1 of formula I, whereinR₀ is hydrogen, chlorine, methyl or methoxy, R₁ is N-(ω-amino-C₂ -C₃ alkyl)-carbamoyl, N-(ω-hydroxy-C₂ -C₃ alkyl)-carbamoyl, hydrazino, 2-hydroxy-propylamino or linear C₂ -C₃ alkylamino that is substituted in the ω-position by 4-morpholinyl, ω-hydroxy-ethylamino, 1H-imidazol-1-yl, 1H-imidazol-4-yl, guanidyl, amino, acetylamino, amidino, carboxy, ethoxycarbonyl, carbamoyl, N-hydroxycarbamoyl, hydroxy or dihydroxyphosphoryloxy, and R₂ is chlorine, trifluoromethyl, carboxy, a radical of the formula --CO₂ R₃ wherein R₃ is methyl, or a radical of the formula --C(═O)--NH--(CH₂)_(n) --R₄ ^(a) wherein n is 2 or 3 and R₄ ^(a) is hydroxy, amino or 1H-imidazol-4-yl, or a salt thereof.
 8. N-(3-chloro-phenyl)-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine or a pharmaceutically acceptable salt thereof according to claim
 1. 9. A compound according to claim 1 of formula I or a pharmaceutically acceptable salt thereof, selected fromN-(3-trifluoromethyl-phenyl)-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N-(3-chloro-phenyl)-4- 2-(2-amino-ethyl-amino)-4-pyridyl!-2-pyrimidineamine N-(3-trifluoromethyl-phenyl)-4- 2-(2-ammino-ethyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4- 2-(N-{2-amino-ethyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4- 2-(N-{2-hydroxy-ethyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine N- 3-chloro-phenyl!-4- 2-(N-{3-hydroxy-propyl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4- 2-(N-{3-amino-prop-1-yl}-aminocarbonyl)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4- 2-(2-hydroxy-ethyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-carboxy-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-methoxycarbonyl-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4- 2-(4-hydroxy-butyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4-{2- 2-(imidazol-4-yl)-ethyl-amino!-4-pyridyl}-2-pyrimidineamine, N- 3-methyl-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4- 2-(5-hydroxy-pentyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-{N-(3-hydroxy-propyl) amino-carbonyl}-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-{N-(3-amino-propyl)aminocarbonyl}-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-{N-(2-imidazol-4-yl-ethyl)-aminocarbonyl}-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-6-methyl-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3,6-dichloro-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-6-methoxy-phenyl!-4- 2-(3-hydroxy-propyl-amino)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4- 2-(1-piperazinyl)-4-pyridyl!-2-pyrimidineamine, N- 3-chloro-phenyl!-4-(2- 2-{4-morpholinyl}ethyl-amino!-4-pyridyl)-2-pyrimidineamine, N- 3-chloro-phenyl!-4-{2- 4-(2-amino-ethyl)-piperazin-1-yl)!-4-pyridyl}-2-pyrimidineamine, N- 3-chloro-phenyl!-4-{2- 3-(2-hydroxy-ethyl-amino)-propylamino!-4-pyridyl}-2-pyrimidineamine and N- 3-chloro-phenyl!-4- 2-(4-morpholinyl)-4-pyridyl!-2-pyrimidineamine and from the pharmaceutically acceptable salts thereof.
 10. The N-phenyl-2-pyrimidine formula I according to claim 1 wherein said derivative comprises N-(3-chloro-phenyl)-4- 2-(2-carboxy-ethyl-amino)-4-pyridyl!-2-pyrimidineamine or a pharmaceutically acceptable salt of said derivative.
 11. A process for the preparation of an N-phenyl-2-pyrimidineamine derivative of formula I ##STR25## wherein R₀ is hydrogen, halogen, lower alkoxy or lower alkyl,R₁ isa) hydrazino, b) cyclohexyl-amino that is unsubstituted or substituted by amino, or c) lower alkylamino substituted by morpholinyl, hydroxy-lower alkylamino, cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxycarbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, lower alkanoylpiperazinyl, formylpiperazinyl, protylamido or by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and R₂ is C₁ -C₆ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxy, phenyl, amino, mono(C₁ -C₃ alkyl)amino, di(C₁ -C₃ alkyl)amino, C₂ -C₄ alkanoyl, propenyloxy, carboxy, carboxy-methoxy, ethoxycarbonyl-methoxy, sulfanilamido, N,N-di(C₁ -C₃ alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formula e:--CO₂ R₃, --NH--C(═O)--R₃, --N(R₃)--C(═O)--R₄, --O--CH₂)_(n) --N(R₃)--R₄, --C(═O)--NH--(CH₂)_(n) --R₄ ^(a), --C(═O)--NH--(CH₂)_(n) --R₃)--R₄, --CH(CH₃)--NH--CHO, --C(CH₃)═N--OH, --C(CH₃)═N--O--CH₃, --CH(CH₃)--N₂, --NH--CH₂ --C(═O)--N(R₃)--R₄, ##STR26## wherein R₃ and R₄ are each independently of the other C₁ -C₃ alkyl, R₄ ^(a) is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R₅ is hydrogen, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine or trifluoromethyl, R₆ is 1H-imidazol-1-yl or morpholinyl and R₇ is C₁ -C₃ alkyl or phenyl unsubstituted or mono-substituted by C₁ -C₃ alkyl, by halogen or by trifluoromethyl, or a salt thereof, whereina) a compound of formula IV ##STR27## wherein Y is the group formed by having a hydroxy group esterified by a strong inorganic or organic acid and the functional groups present in the compound of formula IV, with the exception of the leaving group participating in the reaction, being, if necessary, in protected form, or a salt of the compound of formula IV, is reacted with an amine of formula V

    H.sub.2 N--R.sub.12                                        (V)

wherein R₁₂ is amino or unsubstituted or amino-substituted cyclohexyl, or is lower alkyl that is substituted by morpholinyl, hydroxy-lower alkylamino, cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclo-hexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, the functional groups present in R₁₂ being, if necessary, in protected form; and removing the protecting groups, if present, to obtain the compound of formula I or the salt of the compound of formula I.
 12. A process according to claim 11 for the preparation of a compound of formula Ia ##STR28## wherein R₁ isa) hydrazino, b) cyclohexyl-amino that is unsubstituted or substituted by amino, or c) lower alkylamino that is substituted by cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, di-hydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, propyl-amido or by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ -alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and R₂ is C₁ -C₆ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxy, phenyl, amino, mono(C₁ -C₃ alkyl)amino, di(C₁ -C₃ alkyl)amino, C₂ -C₄ alkanoyl, propenyloxy, carboxy, carboxy-methoxy, ethoxycarbonyl-methoxy, sulfanilamido, N,N-di(C₁ -C₃ alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formula e:--CO₂ R₃, --NH--C(═O)--R₃, --N(R₃)--C(═O)--R₄, --O--(CH₂)_(n) --N(R₃)--R₄, --C(═O)--NH--(CH₂)_(n) --N(R₃)--R₄, --CH(CH₃)--NH--CHO, --C(CH₃)═N--OH, --C(CH₃)═N--O--CH₃, --CH(CH₃)--NH₂, --NH--CH₂ --C(═O)--N(R₃)--R₄, ##STR29## wherein R₃ and R₄ are each independently of the other C₁ -C₃ alkyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R₅ is hydrogen, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, chlorine, bromine, iodine or trifluoromethyl, R₆ is 1H-imidazol-1-yl or morpholinyl, and R₇ is C₁ -C₃ alkyl or is phenyl that is unsubstituted or mono-substituted by C₁ -C₃ alkyl, halogen or by trifluoromethyl, or a salt thereof, whereina) a compound of formula II ##STR30## wherein R₈ and R₉ are each independently of the other lower alkyl and R₁ is as defined above, functional groups present in a compound of formula II, with the exception of the groups participating in the reaction, being, if necessary, in protected form, or a salt of such a compound is reacted with a compound of formula IIIa ##STR31## wherein R₂ is as defined above, functional groups present in a compound of formula IIIa, with the exception of the guanidino group participating in the reaction, being, if necessary, in protected form, or with a salt of such a compound, and any protecting groups present are removed, or a compound of formula IVa ##STR32## wherein Y is the group formed by having a hydroxy group esterified by a strong inorganic or organic acid and R₂ is as defined above, the functional groups present in the compound of formula IVa, with the exception of the leaving group participating in the reaction, being, if necessary, in protected form, or a salt of the compound of formula IVa is reacted with an amine of formula V

    H.sub.2 N--R.sub.12                                        (V)

wherein R₁₂ is amino or unsubstituted or amino-substituted cyclohexyl, or is lower alkyl that is substituted by cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylaminocarbonylamino, amidino, di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical of the formula H₂ N--CH(R)--C(═O)--NH-- wherein R is hydrogen, C₁ -C₄ alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, functional groups present in R₁₂ being, if necessary, in protected form, and removing the protecting groups, if present, to obtain the compound of formula I or the salt of the compound of formula I.
 13. The process according to claim 11 wherein said process further comprises the step of treating the compound of formula I into the salt of the compound of formula I or the step of treating the salt of the compound of formula I into the compound of formula I.
 14. The process according to claim 11 wherein said strong inorganic or organic acid is a hydrohalic acid.
 15. The process according to claim 14 wherein said group formed by having a hydroxy group esterified by said hydrohalic acid is a halogen.
 16. The process according to claim 15 wherein said halogen is chlorine.
 17. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group together with a pharmaceutical carried.
 18. A pharmaceutical composition for the treatment of tumours in warm-blooded animals including humans, comprising a dose effective against a tumour of the bladder or skin of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt of said compound having at least one salt-forming group, together with a pharmaceutical carrier.
 19. The pharmaceutical composition of claim 11 comprising a dose of approximately 1 to 1000 mg of said compound of formula I per 70 kg of body weight.
 20. The pharmaceutical composition of claim 11 comprising a dose of approximately 50 to 500 mg of said compound of formula I per 70 kg of body weight.
 21. A method of treating a warm-blooded animal including a human, which comprises administering to a warm-blooded animal suffering from a tumour of the bladder or the skin a dose effective against said tumour of the bladder or skin of a compound of formula I according to claim 11, or of a pharmaceutically acceptable salt of said compound having at least one salt-forming group.
 22. A pharmaceutical composition for the treatment of tumours in warm-blooded animals including humans, comprising a dose effective against epithelial carcinomas of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt of said compound having at least one salt-forming group together with a pharmaceutical carrier.
 23. A method of treating a warm-blooded animal including a human, which comprises administering to a warm-blooded animal suffering from an epithelial carcinoma disease a dose effective against said disease of a compound of formula I according to claim 1 or of a pharmaceutically acceptable salt of said compound having at least one salt-forming group. 